Heterocyclic substituted piperazine compounds with CXCR3 antagonist activity

ABSTRACT

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: 
                         
or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, zenograft rejection), infectious diseases (e.g., tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/831,053 filed Jul. 14, 2006, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic substitutedpiperazines with CXCR3 antagonist activity, pharmaceutical compositionscontaining one or more such antagonists, one or more such antagonists incombination with other compounds with chemokine activity, one or moresuch antagonists in combination with known immunosuppressive agents,non-limiting example(s) include Methotrexate, interferon, cyclosporin,FK-506 and FTY720, methods of preparing such antagonists and methods ofusing such antagonists to modulate CXCR3 activity. This invention alsodiscloses methods of using such CXCR3 antagonists for the treatment(non-limiting examples include palliative, curative and prophylactictherapies) of diseases and conditions where CXCR3 has been implicated.Diseases and conditions where CXCR3 has been implicated include but arenot limited to inflammatory conditions (psoriasis and inflammatory boweldisease), autoimmune disease (multiple sclerosis, rheumatoid arthritis),fixed drug eruptions, cutaneous delayed-type hypersensitivity responses,type I diabetes, viral meningitis and tuberculoid leprosy. CXCR3antagonist activity has also been indicated as a therapy for tumorgrowth suppression as well as graft rejection (allograft and zenograftrejections for example).

BACKGROUND OF THE INVENTION

Chemokines constitute a family of cytokines that are produced ininflammation and regulate leukocyte recruitment (Baggiolini, M. et al,Adv. Immunol., 55; 97-179 (1994); Springer, T. A., Annual Rev. Physio.,57: 827-872 (1995); and Schall, T. J. and K. B. Bacon, Curr. Opin.Immunol, 6: 865-873 (1994)). Chemokines are capable of selectivelyinducing chemotaxis of the formed elements of the blood (other than redblood cells), including leukocytes such as neutrophils, monocytes,macrophages, eosinophius, basophils, mast cells, and lymphocytes, suchas T cells and B cells. In addition to stimulating chemotaxis, otherchanges can be selectively induced by chemokines in responsive cells,including changes in cell shape, transient rises in the concentration ofintracellular free calcium ions ([Ca²⁺]_(i)), granule exocytosis,integrin upregulation, formation of bioactive lipids (e.g.,leukotrienes) and respiratory burst, associated with leukocyteactivation. Thus, the chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation.

Chemokines are related in primary structure and share four conservedcysteines, which form disulfide bonds. Based upon this conservedcysteine motif, the family can be divided into distinct branches,including the C—X—C chemokines (α-chemokines) in which the first twoconserved cysteines are separated by an intervening residue (e.g., IL-8,IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GROα, GROβ, GROδ, NAP-2, NAP-4),and the C—C chemokines (β-chemokines), in which the first two conservedcysteines are adjacent residues (e.g., MIP-1α, MIP-1β, RANTES, MICP-1,MCP-2, MCP-3, I-309) (Baggiolini, M. and Dahinden, C. A., ImmunologyToday, 15: 127-133 (1994)). Most CXC-chemokines attract neutrophilleukocytes. For example, the CXC-chemokines interleukin-8 (IL-8), GROalpha (GROα), and neutrophil-activating peptide 2 (NAP-2) are potentchemoattractants and activators of neutrophils. The CXC-chemokinesdesignated Mig (monokine induced by gamma interferon) and IP-10(interferon-gamma inducible 10 kDa protein) are particularly active ininducing chemotaxis of activated peripheral blood lymphocytes.

CC-chemokines are generally less selective and can attract a variety ofleukocyte cell types, including monocytes, eosinophils, basophils, Tlymphocytes and natural killer cells. CC-chemokines such as humanmonocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES(Regulated on Activation, Normal T Expressed and Secreted), and themacrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) have beencharacterized as chemoattractants and activators of monocytes orlymphocytes, but do not appear to be chemoattractants for neutrophils,

A chemokine receptor that binds the CXC-chemokines IP-10 and Mig hasbeen cloned, characterized (Loetscher, M. et al., J. Exp. Med., 184:963-969 (1996)) and designated CXCR3. CXCR3 is a G-protein coupledreceptor with seven transmembrane-spanning domains and has been shown tobe restrictively expressed in activated T cells, preferentially humanTh1 cells. On binding of the appropriate ligand, chemokine receptorstransduce an intracellular signal through the associated G-proteinresulting in a rapid increase in intracellular calcium concentration.

The CXCR3 receptor mediates Ca²⁺ (calcium ion) mobilization andchemotaxis in response to IP-10 and Mig. CXCR3 expressing cells show nosignificant response to the CXC-chemokines IL-8, GROα, NAP-2, GCP-2(granulocyte chemotactic protein-2), ENA78 (epithelial-derivedneutrophil-activating peptide 78), PF4 (platelet factor 4), or theCC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1α, MIP-1β, RANTES, I309,eotaxin or lymphotactin. Moreover, a third ligand for CXCR3, I-TAC(Interferon-inducible T cell Alpha Chemoattractant), has also been foundto bind to the receptor with high affinity and mediate functionalresponses (Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

The restricted expression of human CXCR3 in activated T lymphocytes andthe ligand selectivity of CXCR3 are noteworthy. The human receptor ishighly expressed in IL-2 activated T lymphocytes, but was not detectedin resting T lymphocytes, monocytes or granulocytes (Gin, S. et al., J.Clin. Invest., 101: 746-754 (1998)). Additional studies of receptordistribution indicate that it is mostly CD3⁺ cells that express CXCR3,including cells which are CD95⁺, CD45RO⁺, and CD45RA^(low), a phenotypeconsistent with previous activation, although a proportion of CD20⁺ (B)cells and CD56⁺ (NK) cells also express this receptor. The selectiveexpression in activated T lymphocytes is of interest, because otherreceptors for chemokines which have been reported to attract lymphocytes(e.g., MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, RANTES) are also expressedby granulocytes, such as neutrophils, eosinophils, and basophils, aswell as monocytes. These results suggest that the CXCR3 receptor isinvolved in the selective recruitment of effector T cells.

CXCR3 recognizes unusual CXC-chemokines, designated IP-10, Mig andI-TAC. Although these belong to the CXC-subfamily, in contrast to IL-8and other CXC-chemokines which are potent chemoattractants forneutrophils, the primary targets of IP-10, Mig and I-TAC arelymphocytes, particularly effector cells such as activated or stimulatedT lymphocytes and natural killer (NK) cells (Taub, D. D. et al., J. Exp.Med., 177: 18090-1814 (1993); Taub, D. D. et al., J. Immunol., 155:3877-3888 (1995); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021(1998)). (NK cells are large granular lymphocytes, which lack a specificT cell receptor for antigen recognition, but possess cytolytic activityagainst cells such as tumor cells and virally infected cells.)Consistently, IP-10, Mig and I-TAC lack the ELR motif, an essentialbinding epitope in those CXC-chemokines that efficiently induceneutrophil chemotaxis (Clark-Lewis, I. et al., J. Biol. Chem. 266:23128-23134 (1991); Hebert, C. A. et al., J. Biol. Chem., 266:18989-18994 (1991); and Clark-Lewis, 1. et al., Proc. Natl. Acad. Sci.USA, 90: 3574-3577 (1993)). In addition, both recombinant human Mig andrecombinant human IP-10 have been reported to induce calcium flux intumor infiltrating lymphocytes (TIL) (Liao, F. et al., J Exp. Med, 1821301-1314 (1995)). While IP-10 has been reported to induce chemotaxis ofmonocytes in vitro (Taub, D. D. et al. J. Exp. Med., 177: 1809-1814(1993), the receptor responsible has not been identified), human Mig andI-TAC appear highly selective, and do not show such an effect (Liao, F.et al., J. Exp. Med., 182: 1301-1314 (1995); Cole, K. E. et al., J. Exp.Med., 187: 2009-2021 (1998)). IP-10 expression is induced in a varietyof tissues in inflammatory conditions such as psoriasis, fixed drugeruptions, cutaneous delayed-type hypersensitivity responses andtuberculoid leprosy as well as tumors and in animal model studies, forexample, experimental glomerulonephritis, and experimental allergicencephalomyelitis. IP-10 has a potent in vivo antitumor effect that is Tcell dependent, is reported to be an inhibitor of angiogenesis in vivoand can induce chemotaxis and degranulation of NK cells in vitro,suggesting a role as a mediator of NK cell recruitment and degranulation(in tumor cell destruction, for example) (Luster, A. D. and P. Leder, J.Exp. Med., 178: 1057-1065 (1993); Luster, A. D. et al., J Exp. Med. 182:219-231 (1995); Angiolillo, A. L. et al., J. Exp. Med., 182: 155-162(1995); Taub, D. D. et al., J. Immunol., 155: 3877-3888 (1995)). Theexpression patterns of IP-10, Mig and I-TAC are also distinct from thatof other CXC chemokines in that expression of each is induced byinterferon-gamma (IFNδ), while the expression of IL-8 is down-regulatedby IFNδ (Luster, A. D. et al., Nature, 315: 672-676 (1985); Farber, J.M., Proc. Natl. Acad. Sci. USA, 87: 5238-5242 (1990); Farber, J. M.,Biochem. Biophys. Res. Commun., 192 (1): 223-230 (1993), Liao, F. etal., J. Exp. Med., 182: 1301-1314 (1995); Seitz, M. et al., J. Clin.Invest., 87: 463-469 (1991); Galy, A. H. M. and H. Spits, J. Immunol.,147: 3823-3830 (1991); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021(1998)).

Chemokines are recognized as the long-sought mediators for therecruitment of lymphocytes. Several CC-chemokines were found to elicitlymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060(1994)), however, they are also active on granulocytes and monocytes(Uguccioni, M. et al., Eur. J. Immunol., 25: 64-68 (1995); Baggiolini,M. and C. A. Dahinden, Immunol. Today, 15: 127-133 (1994)). Thesituation is different for IP-10, Mig and I-TAC, which are selective intheir action on lymphocytes, including activated T lymphocytes and NKcells, and which bind CXCR3, a receptor which does not recognizenumerous other chemokines and which displays a selective pattern ofexpression.

In view of these observations, it is reasonable to conclude that theformation of the characteristic infiltrates in inflammatory lesions,such as, for example, delayed-type hypersensitivity lesions, sites ofviral infection and certain tumors is a process mediated via CXCR3 andregulated by CXCR3 expression. Lymphocytes, particularly T lymphocytes,bearing a CXCR3 receptor as a result of activation can be recruited intoinflammatory lesions, sites of infection and/or tumors by IP-10, Migand/or I-TAC, which can be induced locally by interferon-gamma. Thus,CXCR3 plays a role in the selective recruitment of lymphocytes,particularly effector cells such as activated or stimulated Tlymphocytes. Accordingly, activated and effector T cells have beenimplicated in a number of disease states such as graft-rejection,inflammation, rheumatoid arthritis, multiple sclerosis, inflammatorybowel disease and psoriasis. Thus, CXCR3 represents a promising targetfor the development of novel therapeutics.

Reference is made to PCT Publication No. WO 93110091 (Applicant: GlaxoGroup Limited, Published May 27, 1993) which discloses piperidine aceticacid derivatives as inhibitors of fibrinogen-dependent blood plateletaggregation having the formula:

An illustrative compound of that series is:

Reference is also made to PCT Publication No. WO 99/20606 (Applicant: J.Uriach & CIA. S. A., Published Apr. 29, 1999) which disclosespiperazines as platelet aggregation inhibitors having the formula:

Reference is also made to US Patent Application No. US 2002/0018776 A1(Applicant. Hancock, et al. Published Feb. 14, 2002) which disclosesmethods of treating graft rejection.

Reference is also made to PCT Publication No. WO 031098185 A2(Applicant: Renovar, Inc., Published Nov. 27, 2003) which disclosesmethods of diagnosing and predicting organ transplant rejection bydetection of chemokines, for example, CXCR3 and CCL chemokines in urine.

Reference is also made to PCT Publication No. WO 03/082335 A1(Applicant: Sumitomo Pharmaceuticals Co. Ltd., Published Oct. 9, 2003)which discloses methods of screening a CXCR3 ligand and methods ofdiagnosing type 2 diabetes by detecting the expression dose of a CXCR3ligand in a biological sample.

Reference is also made to PCT Publication No. WO 02/085861 (Applicant:Millennium Pharmaceuticals, Inc. Published Oct. 31, 2002) whichdiscloses imidazolidine compounds and their use as CXCR3 antagonistshaving the formula:

An illustrative compound of that series is:

Reference is also made to PCT Publication No. WO 03/101970 (Applicant:SmithKline Beecham Corporation, Published Dec. 11, 2003) which disclosesimidazolium compounds and their use as CXCR3 antagonists having theformula:

An illustrative example of that series is:

Reference is also made to US Patent Application No. US 2003/0055054 A1(Applicant: Medina et al., Published Mar. 20, 2003) and related patentU.S. Pat. No. 6,794,379 B2 ((Applicant: Medina et al, Published Sep. 21,2004) which discloses compounds with CXCR3 activity having the formula:

An illustrative compound of that series is:

Reference is also made to U.S. Pat. No. 6,124,319 (Applicant: MacCoss etal., issued Sep. 6, 2000) which discloses compounds useful as chemokinereceptor modulators having the formula:

Reference is also made to PCT Publication WO 03/070242 A1 (Applicant:CELLTECH R&D limited, Published Aug. 28, 2003) which discloses compoundsuseful as “chemokine receptor inhibitors for the treatment ofinflammatory diseases” having the formula:

Reference is also made to PCT Publication WO 041074287 A1, WO 04/074273A1, WO 04/74278 (Applicant: AstraZeneca R&D Published Feb. 19, 2004)which discloses pyridine derivatives, processes for their preparationand use in the modulation of autoimmune disease, having the formula.

where R3 is phenyl, or a 5- or 6-membered aromatic ring with 1 or morenitrogen atoms.

Reference is also made to U.S. Patent Application PublicationUS2006/0036093 A1, published Feb. 16, 2006, which refers to certainpyrimidone compounds binding to CXCR3 receptors.

There is a need for compounds that are capable of modulating CXCR3activity. For example, there is a need for new treatments and therapiesfor diseases and conditions associated with CXCR3 such as inflammatoryconditions (psoriasis and inflammatory bowel disease), autoimmunedisease (multiple sclerosis, rheumatoid arthritis) and graft rejection(allograft and zenograft rejections for example) as well as infectiousdiseases, cancers and tumors, fixed drug eruptions, cutaneousdelayed-type hypersensitivity responses, type I diabetes, viralmeningitis and tuberculoid leprosy.

There is a need for methods of treatment or prevention or ameliorationof one or more symptoms of diseases and conditions associated withCXCR3. There is a need for methods for modulating CXCR3 activity usingthe compounds provided herein.

SUMMARY OF THE INVENTION

In its many embodiments, the invention provides novel compounds ofFormula 1:

or a pharmaceutically acceptable salt, solvate or ester thereof wherein:

G is —C≡N or

X is N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl orheterocyclenyl;

Z is N, or NO;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, alkyl, alkoxy,alkenyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino,-alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, —N≡CH, ═NCN,—(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹,—(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, —C(═S)N(H)alkyl,—N(H)—S(O)₂-alkyl, —N(H)C(═O)N(H)-alkyl, —S(O)₂alkyl, —S(O)₂N(H)alkyl,—S(O)₂N(alkyl)₂, —S(O)₂aryl, —C(═S)N(H)cycloalkyl, —C(═O)N(H)NH₂,—C(═O)alkyl, —C(═O)aryl, —C(═O)heteroalkyl, heteroaryl, heterocyclyl,and heterocyclenyl; or alternatively when X is N, the N taken togetherwith the R¹ and R² forms a cycloalkyl, heterocyclyl, heteroaryl or—N═C(NH₂)₂,

R³, R⁵ and R⁶ moieties can be the same or different, each beingindependently selected from the group consisting of H, alkyl, alkylaryl,aralkyl, —C(═O)alkyl, —CN, CF₃, OCF₃, haloalkyl, cycloalkyl, halogen,hydroxyalkyl, —N═CH—(R³¹), —C(═O)N(R³⁰)₂, —N(R³⁰)₂, —NSO₂R³¹, —OR³⁰,—SO₂(R³¹), —SO₂NHR³⁰, —N(R³⁰)C(═O)N(R³⁰)₂ and —N(R³⁰)C(═O)R³¹;

R⁷ and R⁸ are the same or different, each being independently selectedfrom the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxyl,—CN, alkoxy, —N(R³⁰)₂, —N(H)S(O)₂alkyl, —N(H)C(═O)N(H)alkyl,—(CH₂)_(q)OH, —(CH₂)_(q)Oalkyl, —(CH₂)_(q)N(H)-alkyl,—(CH₂)_(q)N(H)—S(O)₂alkyl, and —(CH₂)_(q)N(H)—CO—N(H)alkyl; oralternatively R⁷ and R⁸ taken together with the carbon atom to whichthey are shown attached is ═O, ═S, ═NH, ═N(alkyl), ═N(Oalkyl), ═N(OH) orcycloalkyl;

the R¹⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO₂H,hydroxyl, alkoxy, hydroxyalkyl, —N(R³⁰)₂, —C(═O)N(R³⁰)₂, —(CH₂)_(q)OH,—(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³, —(CH₂)_(q)N(R³¹)₂, —OR³⁰, halogen, and—C(═O)R³¹; or wherein two R¹⁰ moieties together on the same carbon atomform ═O;

the R¹¹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl,hydroxyalkyl, hydroxyl, alkoxy, carboxamide, —N(R³⁰)₂, CO₂H,—(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)N(R³¹)₂, —OR³⁰,halogen, and —C(═O)R³¹; or wherein two R¹¹ moieties together on the samecarbon atom form ═O;

R¹² is selected from the group consisting of H, alkyl, haloalkyl —CN,CF₂H, CF₃, —C(═O)N(R³⁰)₂, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹.—(CH₂)_(q)N(R³¹)₂, and —S(O₂)R³¹;

D is a three to nine membered cycloalkyl, three to nine memberedcycloalkenyl, or a five to eight membered aryl, heteroaryl,heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms or moietiesindependently selected from the group consisting of N, O, S and SO₂,wherein ring D is unsubstituted or optionally substituted with 1-5independently selected R²⁰ moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, -alkylamino, -alkylthiocarboxy, alkylheteroaryl, alkylthio,alkylsulfinyl-, —C(═O)—O-alkyl, amidinyl, aralkyl, aralkenyl, aralkoxy,aralkoxycarbonyl, aralkylthio, aryl, cyano, cycloalkyl, cycloalkenyl,guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl,heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro,trifluoromethoxy, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)N H₂,—(CH₂)_(q)NHR³¹, —(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —C(═NR³⁰)NHR³⁰,—C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂, —C(═O)OR³⁰, —N(R³⁰)₂,—N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹), —N(R³⁰)C(═O)N(R³⁰)₂,—N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, —SR³⁰,—SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹), and —OSi(R³⁰)₃; or alternatively twoR²⁰ moieties are linked together to form a five or six membered aryl,cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring whereinsaid five or six membered aryl, cycloalkyl, heterocyclyl,heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ringis optionally substituted with 0-4 R²¹ moieties;

the R²¹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, -alkylamino, -alkylthiocarboxy, alkylheteroaryl, alkylthio,alkylsulfinyl-, —C(═O)—O-alkyl, amidinyl, aralkyl, aralkenyl, aralkoxy,aralkoxycarbonyl, aralkylthio, aryl, cyano, cycloalkyl, cycloalkenyl,guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl,heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy,—(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹,—(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, -alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰,—C(═O)N(R³⁰)₂, —C(═NR³⁰)NHR³⁰, —C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂,—C(═O)OR³⁰, —N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂,—N(R³⁰)C(═O)OR³¹, —N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹),—N(R³⁰)C(═O)N(R³⁰)₂, —N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰,—OC(═O)N(R³⁰)₂, —SR³⁰, —SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹), and—OSi(R³⁰)₃;

Y is selected from the group consisting of —(CR¹³R¹³)_(r)—, —CHR³C(═O)—,—(CHR¹³)_(r)O—, —(CHR¹³)_(r)N(R³⁰)—, —C(═O)—, —C(═NR³⁰)—, —C(═N—OR³⁰)—,—CH(C(═O)NHR³⁰)—, CH-heteroaryl-, —C(R¹³R¹³)_(r)C(R¹³)═C(R¹³)—,—(CHR¹³)—_(r)C(═O)— and —(CHR¹³)—_(r)N(H)C(═O)—; or alternatively Y iscycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl,heterocyclenyl, or heterocyclyl is fused with ring D;

the R¹³ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, cycloalkyl,alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, —CN,—CO₂H, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —(CHR³⁰)_(q)OH, —(CHR³⁰)_(q)OR³¹,—(CHR³⁰)_(q)NH₂, —(CHR³⁰)_(q)NHR³¹, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, —NH₂, —N(R³⁰)₂,—N(R³⁰)C(═O)N(R³⁰)₂, —N(R³⁰)SO₂(R³¹), —OH, OR³⁰, —SO₂N(R³⁰)₂, and—SO₂(R³¹);

the R³⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, aryl,aralkyl, cycloalkyl, CN, —(CH₂)_(q)OH, —(CH₂)_(q)Oalkyl,—(CH₂)_(q)Oalkylaryl, —(CH₂)_(q)Oaryl, —(CH₂)_(q)Oaralkyl,—(CH₂)_(q)Ocycloalkyl, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHalkyl,—(CH₂)_(q)N(alkyl)₂, —(CH₂)_(q)NHalkylaryl, —(CH₂)_(q)NHaryl,—(CH₂)_(q)NHaralkyl, —(CH₂)_(q)NHcycloalkyl, —(CH₂)_(q)C(═O)NHalkyl,—(CH₂)_(q)C(═O)N(alkyl)₂, —(CH₂)_(q)C(═O)NHalkylaryl,—(CH₂)_(q)C(═O)NHaryl, —(CH₂)_(q)C(═O)NHaralkyl,—(OH₂)_(q)C(═O)NHcycloalkyl, —(CH₂)_(q)SO₂alkyl, —(CH₂)_(q)SO₂alkylaryl,—(CH₂)_(q)SO₂aryl, —(CH₂)_(q)SO₂aralkyl, —(CH₂)_(q)SO₂cycloalkyl,—(CH₂)_(q)NSO₂alkyl, —(CH₂)_(q)NSO₂alkylaryl, —(CH₂)_(q)NSO₂aryl,—(CH₂)_(q)NSO₂aralkyl, —(CH₂)_(q)NSO₂cycloalkyl, —(CH₂)_(q)SO₂NHalkyl,—(CH₂)_(q)SO₂NHalkylaryl, —(CH₂)_(q)SO₂NHaryl, —(CH₂)_(q)SO₂NHaralkyl,—(CH₂)_(q)SO₂NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

the R³¹ moieties can be the same or different, each being independentlyselected from the group consisting of alkyl, alkylaryl, aryl, aralkyl,cycloalkyl, —(CH₂)_(q)OH, —(CH₂)_(q)Oalkyl, —(CH₂)_(q)Oalkylaryl,—(CH₂)_(q)Oaryl, —(CH₂)_(q)Oaralkyl, —(CH₂)_(q)Ocycloalkyl,—(CH₂)_(q)NH₂, —(CH₂)_(q)NHalkyl, —(CH₂)_(q)N(alkyl)₂,—(CH₂)_(q)NHalkylaryl, —(CH₂)_(q)NHaryl, —(CH₂)_(q)NHaralkyl,—(CH₂)_(q)NHcycloalkyl, —(CH₂)_(q)C(═O)NHalkyl,—(CH₂)_(q)C(═O)N(alkyl)₂, —(CH₂)_(q)C(═O)NHalkylaryl,—(CH₂)_(q)C(═O)NHaryl, —(CH₂)_(q)C(═O)NHaralkyl,—(CH₂)_(q)C(═O)NHcycloalkyl, —(CH₂)_(q)SO₂alkyl, —(CH₂)_(q)SO₂alkylaryl,—(CH₂)_(q)SO₂aryl, —(CH₂)_(q)SO₂aralkyl, —(CH₂)_(q)SO₂cycloalkyl,—(CH₂)_(q)NSO₂alkyl, —(CH₂)_(q)NSO₂alkylaryl, —(CH₂)_(q)NSO₂aryl,—(CH₂)_(q)NSO₂aralkyl, —(CH₂)_(q)NSO₂cycloalkyl, —(CH₂)_(q)SO₂NHalkyl,—(CH₂)_(q)SO₂NHalkylaryl, —(CH₂)_(q)SO₂NHaryl, —(CH₂)_(q)SO₂NHaralkyl,—(CH₂)_(q)SO₂NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

m is 0 to 4;

n is 0 to 4;

each q can be the same or different, each being independently selectedfrom 1 to 5; and

r is 1 to 4;

with the proviso that when a nitrogen is substituted by two alkylgroups, said two alkyl groups may be optionally joined to each other toform a ring.

A further feature of the invention is a pharmaceutical compositioncontaining as active ingredient at least one compound of Formula 1together with at least one pharmaceutically acceptable carrier orexcipient.

In another embodiment, the invention provides a method of treating aCXCR3 chemokine mediated disease in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of at least one compound of Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof.

In another embodiment, the invention provides a method of inhibiting orblocking T-cell mediated chemotaxis in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

The invention also provides a method of modulating (inhibiting orpromoting) an inflammatory or immune response in an individual in needof such therapy, comprising administering a therapeutically effectiveamount of a compound of Formula 1 or a pharmaceutically acceptable salt,solvate or ester thereof.

Also disclosed is a method of treating inflammatory bowel disease (suchCrohn's disease, ulcerative colitis) in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof.

Also disclosed is a method of treating graft rejection in a patient inneed of such treatment comprising administering to the patient atherapeutically effective amount of at least one compound of Formula 1,or a pharmaceutically acceptable salt, solvate or ester thereof.

DETAILED DESCRIPTION OF THE INVENTION

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“alkoxy,” etc.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Acyl” means an H—C(═O)—, alkyl-C(═O)—, alkenyl-C(═O)—, alkynyl-C(═O)—,cycloalkyl-C(═O)—, cycloalkenyl-C(═O)—, or cycloalkynyl-C(O)— group inwhich the various groups are as previously described. The bond to theparent moiety is through the carbonyl carbon atom. Preferred acylscontain a lower alkyl Non-limiting examples of suitable acyl groupsinclude formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl andcyclohexanoyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched The alkenyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxyl, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano,heteroaryl, heterocyclyl, amino, aminosulfonyl, halo, carboxyl,carboxyalkyl (non-limiting example(s) include ester), alkoxycarbonyl,hydroxyalkyl, carbonyl (non-limiting example(s) include ketone),—C(═O)heterocyclyl, formyl (non-limiting example(s) include aldehyde),carboxamido (i.e. amido, —C(═O)NH₂), —C(═O)N(alkyl)₂, —C(═O)NH(alkyl),—C(═O)N(cycloalkyl)₂, —C(═O)NH(cycloalkyl), —NHC(═O)alkyl, urea (e.g—NH(C═O)NH₂, —NH(C═O)NH(alkyl), —NH(C═O)NH(alkyl)₂,—NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl)), guanidinyl,—NHC(═NCN)NH₂, —NHC(═NCN)N(alkyl)₂, carbamoyl (i.e. —CO₂NH₂),NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O))NH—S(O)₂alkyl,—NHC(═O)N(alkyl)₂—S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)—S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)—S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂, alkylthiocarboxy, —S(O)₂alkyl—S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonyl urea (non-limitingexample(s) include NHC(═S)NHalkyl). Non-limiting examples of suitablealkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,n-pentenyl, octenyl and decenyl.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched or a combination thereof, and comprising about 1 to about 20carbon atoms in the chain. Preferred alkyl groups contain about 1 toabout 12 carbon atoms in the chain. More preferred alkyl groups containabout 1 to about 6 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl or propyl₁ are attached toa linear alkyl chain. “Lower alkyl” means a group having about 1 toabout 6 carbon atoms in the chain which may be straight or branched. Thealkyl group may be substituted by one or more substituents which may bethe same or different, each substituent being independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, aryl,aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl,amino, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —N(cycloalkyl)₂,—NH(aryl), —N(aryl)₂, —NH(heteroaryl), —N(heteroaryl)₂,—NH(heterocyclyl), N(heterocyclyl )₂, halo, hydroxy, carboxyl,carboxyalkyl (non-limiting example(s) include ester), alkoxycarbonyl,hydroxyalkyl, carbonyl (non-limiting example(s) include ketone),—C(═O)heterocyclyl, formyl, carboxamido (i.e. amido, —C(═O)NH₂,—C(═O)N(alkyl)₂, —C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂,—C(═O)NH(cycloalkyl)), —NHC(═O)alkyl, amidinyl, hydrazidyl, hydroxamate,—NHC(═O)H, —NHC(═O)alkyl, urea (e.g —NH(C═O)NH₂, —NH(C═O)NH(alkyl),—NH(C═O)NH(alkyl)₂, —NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl)),guanidinyl, —NHC(═NCN)NH₂, —NHC(═NCN)N(alkyl)₂, carbamoyl (i.e.—CO₂NH₂), —NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O)NH—S(O)₂alkyl,—NHC(═O)N(alkyl)-S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)-S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)-S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂, thio, alkylthio, alkylthiocarboxy,—S(O)alkyl, —S(O)₂alkyl, —S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonylurea (non-limiting example(s) include —NHC(═S)NHalkyl) and OSi(alkyl)₃.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl,fluoromethyl, trifluoromethyl and cyclopropylmethyl.

“Alkylheteroaryl” means an alkyl-heteroaryl- group wherein the alkyl isas previously described and the bond to the parent moiety is through theheteroaryl group.

“Alkylamino” means an —NH₂ or —NH₃+ group in which one or more of thehydrogen atoms on the nitrogen is replaced by an alkyl group as definedabove. The bond to the parent is through the nitrogen.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas described herein. Preferred alkylaryls comprise a lower alkyl group.Non-limiting examples of suitable alkylaryl groups include o-tolyl,p-tolyl and xylyl. The bond to the parent moiety is through the aryl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is asdescribed herein. Non-limiting examples of suitable alkylthio groupsinclude methylthio, ethylthio, i-propylthio and heptylthio. The bond tothe parent moiety is through the sulfur.

“Alkylthiocarboxy” means an alkyl-S—C(═O)O— group. Preferred groups arethose in which the alkyl group is lower alkyl. The bond to the parentmoiety is through the carboxy.

“Alkylsulfonyl” means an alkyl-S(O)₂— group. Preferred groups are thosein which the alkyl group is lower alkyl The bond to the parent moiety isthrough the sulfonyl.

“Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfinyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.The alkynyl group may be substituted by one or more substituents whichmay be the same or different, each substituent being independentlyselected from the group consisting of alkyl, alkoxyl, aryl, aryloxy,cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —N(cycloalkyl)₂, —NH(aryl), —N(aryl)₂,—NH(heteroaryl), —N(heteroaryl)₂, —NH(heterocyclyl), N(heterocyclyl)₂,alkoxycarbonyl, hydroxyalkyl, carbonyl (non-limiting example(s) includeketone), —C(═O)heterocyclyl, carboxamido (i.e. amido, —C(═O)NH₂),—C(═O)N(alkyl)₂, —C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂,—C(═O)NH(cycloalkyl), alkylC(═O)NH—, —NHC(═O)alkyl, urea (e.g—NH(C═O)NH₂), —NH(C═O)NH(alkyl), —NH(C═O)NH(alkyl)₂,—NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl), —S(O)₂alkyl, and—S(O)₂aryl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described, Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy andmethylhydroxy. The bond to the parent moiety is through the etheroxygen.

“Alkoxycarbonyl” means an alkyl-O—C(═O)— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aminoalkyl” means an amine-alkyl- group in which alkyl is as previouslydefined. Preferred aminoalkyls contain lower alkyl. Non-limitingexamples of suitable aminoalkyl groups include aminomethyl and2-Dimethylamino-2-ethyl. The bond to the parent moiety is through thealkyl.

“Amidinyl” means —C(═NR)NHR group. The R groups are defined as H, alkyl,alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, —NHSO₂alkyl,—NHSO₂Aryl, —NHC(═O)NHalkyl, and —NHalkyl. The bond to the parent moietyis through the carbon.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group attached to the aryl group. Non-limiting examples ofsuitable aralkyl groups include benzyl, 2-phenethyl andnaphthalenylmethyl. The bond to the parent moiety is through the alkyl.

“Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as previously described. Preferred aralkenyls contain a loweralkenyl group. Non-limiting examples of suitable aralkenyl groupsinclude 2-phenethenyl and 2-naphthylethenyl. The bond to the parentmoiety is through the alkenyl.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Aralkoxy” means an aralkyl-O— group in which the aralkyl group is asdescribed above. The bond to the parent moiety is through the oxygengroup.

“Aralkoxycarbonyl” means an aralkyl-O—C(═O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Aroyl” means an aryl-C(═O)— group in which the aryl group is aspreviously described The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- and 2-naphthoyl.

“Aryl” (sometimes abbreviated “Ar”) means an aromatic monocyclic ormulticyclic ring system comprising about 6 to about 14 carbon atoms,preferably about 6 to about 10 carbon atoms. The aryl group can beoptionally substituted with one or more “ring system substituents” whichmay be the same or different, and are as defined herein. Non-limitingexamples of suitable aryl groups include phenyl and naphthyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Arylsulfonyl” means an aryl-S(O)₂— group. The bond to the parent moietyis through the sulfonyl.

“Arylsulfinyl” means an aryl-S(O)— group. The bond to the parent moietyis through the sulfinyl.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Carboxyalkyl” means an alkyl-C(═O)O— group. The bond to the parentmoiety is through the carboxy.

Carbamates and urea substituents refer to groups with oxygens andnitrogens respectively adjacent an amide; representative carbamate andurea substituents include the following:

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalin, norbornyl, adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl. The term “cycloalkenyl” additionally means moieties suchas cyclobutenedione, cyclopentenone, cyclopentenedione and the like.

“Halogen” (or halo) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.Non-limiting examples include trifluoromethyl, 2,2,2-trifluoroethyl,2-chloropropyl and alike.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. The nitrogen or sulfur atom ofthe heteroaryl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable heteroarylsinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl,isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Heterocyclenyl” means a partially unsaturated monocyclic or partiallyunsaturated multicyclic ring system comprising about 5 to about 14 ringatoms, preferably about 5 to about 10 ring atoms, in which one or moreof the ring atoms is an element other than carbon, for example nitrogen,oxygen or sulfur, alone or in combination. Preferred heterocyclenylscontain about 5 to about 6 ring atoms and 1-3 double bonds. Preferredheterocyclenyls also contain at least one —C═N as part of the ring. The“heterocyclenyl” can be optionally substituted by one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. The prefix aza, oxa or thia before the heterocyclenylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. The nitrogen or sulfur atom ofthe heteroaryl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitableheterocyclenyls include dihydroimidazole, dihydrooxazole,dihydrooxadiazole, dihydrothiazole, and the like.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The nitrogen or sulfur atom of the heterocyclyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orSS-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like. Also included are ring systemscomprising about 3 to about 10 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the atoms in the ring system isan element other than carbon, for example nitrogen, oxygen or sulfuratom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Non-limiting examples of suitable monocyclic azaheterocyclic (i.e.,azaheterocyclyl) groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, dihydro-2-pyrrolinyl,dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl,dihydro-4,5-trizolyl and the like. Non-limiting examples of suitableoxaheterocyclic (i.e., oxaheterocyclyl) groups include3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and thelike. Non-limiting example of a suitable multicyclic oxaheterocyclicgroup is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclic (i.e., thiaheterocyclyl) rings includedihydrothiophenyl, dihydrothiopyranyl, and the like.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-(3-yl)methyl.The bond to the parent moiety is through the alkyl.

“Heteroaralkenyl” means an heteroaryl-alkenyl- group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl group. Non-limiting examples ofsuitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through thealkenyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl. The bond to the parent moiety is through the alkyl.

“Hydroxamate” means an alkyl-C(═O)NH—O— group. The bond to the parentmoiety is through the oxygen group.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, alkoxyl, aryl, aroyl, aryloxy,cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkylaryl,alkytheteroaryl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, amino,—NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —N(cycloalkyl)₂, —NH(aryl),—N(aryl)₂, —NH(heteroaryl), —N(heteroaryl)₂, —NH(heterocyclyl),N(heterocyclyl)₂, halo, hydroxy, carboxyl, carboxyalkyl (non-limitingexample(s) include ester), cyano, alkoxycarbonyl, hydroxyalkyl, carbonyl(non-limiting example(s) include ketone), —C(═O)heterocyclyl, formyl(non-limiting example(s) include aldehyde), carboxamido (i.e. amido,—C(═O)NH₂), —C(═O)N(alkyl)₂, —C(═O)NH(alkyl), —C(═O)N(cycloalkyl)₂,—C(═O)NH(cycloalkyl), alkylC(═O)NH—, -amidino, hydrazido, hydroxamate,—NHC(═O)H, —NHC(—O)alkyl, urea (e.g —NH(C═O)NH₂), —NH(C═O)NH(alkyl),—NH(C═O)NH(alkyl)₂, —NH(C═O)NH(heteroaryl), —NH(C═O)NH(heterocyclyl),guanidinyl, —NHC(═NCN)NH₂, —NHC(—NCN)N(alkyl)₂, carbamoyl (i.e.—CO₂NH₂), —NHC(═O)Oalkyl, —CO₂N(alkyl)₂, —NHC(═O)NH—S(O)₂alkyl,—NHC(═O)N(alkyl)₂—S(O)₂alkyl, —NH—S(O)₂alkyl, —NH—S(O)₂heteroaryl,—N(alkyl)-S(O)₂alkyl, —NH—S(O)₂aryl, —N(alkyl)—S(O)₂aryl, —NH—S(O)₂NH₂,—NH—S(O)₂NHalkyl, —NH—S(O)₂N(alkyl)₂,thio, alkylthiocarboxy,—S(O)₂alkyl, —S(O)₂aryl, —OS(O)₂alkyl, —OS(O)₂aryl, sulfonyl urea(non-limiting example(s) include —NHC(═S)NHalkyl) and OSi(alkyl)₃.

“Spiroalkyl” means an alkylene group wherein two carbon atoms of analkyl group are attached to one carbon atom of a parent molecular groupthereby forming a carbocyclic or heterocyclic ring of three to elevenatoms. Representative structures include examples such as:

The spiroalkyl groups of this invention can be optionally substituted byone or more ring system substituents, wherein “ring system substituent”is as defined herein.

“Ring system substituent” also means a cyclic ring of 3 to 7 ring atomsof which may contain 1 or 2 heteroatoms, attached to an aryl,heteroaryl, or heterocyclyl ring by simultaneously substituting two ringhydrogen atoms on said aryl, heteroaryl, heterocyclyl ring. Non-limitingexamples include:

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

With reference to the number of moieties (non-limiting example(s)include, substituents, groups or rings) in a compound, unless otherwisedefined, the phrases “one or more” and “at least one” mean that, therecan be as many moieties as chemically permitted, and the determinationof the maximum number of such moieties is well within the knowledge ofthose skilled in the art. Preferably, there are one to threesubstituents, or more preferably, one to two substituents, with at leastone in the para position.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The straight line

as a bond generally indicates a mixture of, or either of, the possibleisomers, non-limiting example(s) include, containing (R)— and (S)—stereochemistry. For example,

A dashed line (

) represents an optional bond.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring atoms, non limiting examples include carbon, nitrogenand sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula 1 or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

“Metabolic conjugates”, for example, glucuronides and sulfates which canundergo reversible conversion to compounds of Formula 1 are contemplatedin this application.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective to antagonize CXCR3 and thus produce the desired therapeuticeffect in a suitable patient.

An “inflammatory disease” is characterized by a local or systemic, acuteor chronic inflammation. An “immune disease” is characterized by ahyper- or hypo-reaction of the immune system. Examples of inflammatoryor immune diseases include neurodegenerative diseases (e.g., Alzheimer'sdisease), multiple sclerosis, systemic lupus erythematosus, rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, juvenilerheumatoid arthritis, atherosclerosis, vasculitis, chronic heartfailure, cerebrovascular ischemia, encephalitis, meningitis, hepatitis,nephritis, sepsis, sarcoidosis, psoriasis, eczema, urticaria, type Idiabetes, asthma, conjunctivitis, ophthalmic inflammation, otitis,allergic rhinitis, chronic obstructive pulmonary disease, sinusitis,dermatitis, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, Behcet's syndrome, pulmonary fibrosis, endometriosis, gout,cancer, cachexia, viral infections, bacterial infections, organtransplant conditions, skin transplant conditions, and graft versus hostdiseases.

“Mammal” means humans and other mammalian animals.

“Patient” includes both human and animals.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid, “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O. In general,the solvated forms are equivalent to the unsolvated forms and areintended to be encompassed within the scope of this invention.

The compounds of Formula 1 form salts which are also within the scope ofthis invention. Reference to a compound of Formula 1 herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula 1 contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (non-limiting example(s) include, non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the Formula 1 may be formed, for example, byreacting a compound of Formula 1 with an amount of acid or base, such asan equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization. Acids(and bases) which are generally considered suitable for the formation ofpharmaceutically useful salts from basic (or acidic) pharmaceuticalcompounds are discussed, for example, by S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. ofPharmaceutics (1986) 33 201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; in The Orange Book(Food & Drug Administration, Washington, D.C. on their website); and P.Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of PharmaceuticalSalts: Properties, Selection, and Use, (2002) Int'l. Union of Pure andApplied Chemistry, pp. 330-331 These disclosures are incorporated hereinby reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulhates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides(non-limiting example(s) include methyl, ethyl, propyl, and butylchlorides, bromides and iodides), dialkyl sulfates (non-limitingexample(s) include dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (non-limiting example(s) include decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(non-limiting example(s) include benzyl and phenethyl bromides), andothers.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino), (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula 1, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations. The use ofthe terms “salt”, “solvate” “prodrug” and the like, is intended toequally apply to the salt, solvate, ester and prodrug of enantiomers,stereoisomers, rotamers, tautomers, racemates or prodrugs of theinventive compounds.

It should also be noted that throughout the specification and Claimsappended hereto any formula, compound, moiety or chemical illustrationwith unsatisfied valences is assumed to have the hydrogen atom tosatisfy the valences unless the context indicates a bond.

In one embodiment, in formula 1, Z is N or NO (i.e., N-oxide).

In another embodiment, in formula 1, G is —C≡N.

In another embodiment, in formula 1, G is

In another embodiment, G is

wherein X is N or O.

In another embodiment, G is

wherein R¹ and R² are independently absent or present, and if presenteach is independently selected from the group consisting of H, alkyl,hydroxyalkyl, and cycloalkyl

In another embodiment, G is

wherein R¹ and R² are independently absent or present, and if presenteach is independently selected from the group consisting of H, —CH₃,—CH₂CH₃, —CH₂CH₂OH, and cyclopropyl.

In another embodiment, in formula 1, R³ is selected from the groupconsisting of H, alkyl, alkoxy, halo, and haloalkyl.

In another embodiment, in formula 1, R³ is selected from the groupconsisting of —H, —CH₃, OCH₃, —Cl and —CF₃.

In another embodiment, in formula 1, wherein R⁵ is selected from thegroup consisting of H, alkyl, —OR³⁰, —N(R³⁰)₂, and halogen.

In another embodiment, in formula 1, wherein R⁵ is H, CH₃, OH, NH₂, andF.

In another embodiment, in formula 1, wherein R⁵ is H.

In another embodiment, in formula 1, R⁶ is selected from the groupconsisting of H, alkyl, —OR³⁰, —N(R³⁰)₂, and halogen

In another embodiment, in formula 1, R⁶ is selected from the groupconsisting of H, CH₃, OH, NH₂, and F.

In another embodiment, in formula 1, R⁶ is selected from the groupconsisting of H and alkyl.

In another embodiment, in formula 1, R⁶ is selected from the groupconsisting of —H and —CH₃.

In another embodiment, in formula 1, G is

wherein R⁷ and R⁸ are both H, or R⁷ and R⁸ taken together with thecarbon atom to which they are shown attached is ═O.

In another embodiment, in formula 1, R¹⁰ is selected from the groupconsisting of alkyl, hydroxyl, and alkoxy, or wherein two R¹⁰ moietiestogether on the same carbon atom form ═O, and m is 1-2.

In another embodiment, in formula 1, R¹⁰ is alkyl, and m is 1-2.

In another embodiment, in formula 1, m is 1-2, and R¹⁰ is selected fromthe group consisting of —CH₃ and —CH₂CH₃.

In another embodiment, in formula 1, R¹¹ is selected from the groupconsisting of H, alkyl, alkoxy, and hydroxyl, or wherein two R¹¹moieties together on the same carbon atom form ═O; and n is 1-2.

In another embodiment, in formula 1, R¹¹ is H and n is 1.

In another embodiment, in formula 1, R¹² is selected from the groupconsisting of H, alkyl, and haloalkyl.

In another embodiment, in formula 1, R¹² is H, CH₃, or CF₃.

In another embodiment, in formula 1, R¹² is H.

In another embodiment, in formula 1, Y is selected from the groupconsisting of: —(CHR¹³)_(r)— and —C(═O)—.

In another embodiment, in formula 1, Y is selected from the groupconsisting of: —CH₂— and —C(═O)—.

In another embodiment, in formula 1, D is 5 to 9 membered aryloptionally substituted with 1-2 R²⁰ moieties selected independently fromthe group consisting of halogen, —OR³⁰, alkyl, —N(R³⁰)₂, haloalkyl,cyano, —SO₂(R³¹), —SO₂N(R³⁰)₂, and haloalkoxy.

In another embodiment, in formula 1, D is 5 to 9 membered aryloptionally substituted with 1-2 R²⁰ moieties selected independently fromthe group consisting of halogen, hydroxyl, alkyl, alkoxy, aminoalkyl,haloalkyl, cyano, sulfonylalkyl, sulfonylamino and haloalkoxy.

In another embodiment, in formula 1, D is 5 to 9 membered aryloptionally substituted with 1-2 R²⁰ moieties selected independently fromthe group consisting of halogen, alkyl, haloalkyl, and haloalkoxy. Inanother embodiment, in formula 1, D is 5 to 9 membered aryl optionallysubstituted with 1-2 R²⁰ moieties selected independently from the groupconsisting of halogen, hydroxyl, alkyl, alkoxy, aminoalkyl, haloalkyl,cyano, sulfonylalkyl, sulfonylamino and haloalkoxy.

In another embodiment, in formula 1, D is phenyl, substituted with 1-2moieties selected independently from the group consisting of alkyl,alkoxy, —Cl, —F, and trifluoromethoxy.

In another embodiment, in formula 1,

Z is N or NO;

G is

X is N or O;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, alkyl, aryl andcycloalkyl or alternatively when X is N, the N taken together with theR¹ and R² forms a cycloalkyl or a heterocyclyl;

oalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl,hydroxyalkyl, trifluoromethoxy, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NHR³¹,—(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹, —(CH₂)_(q)SO₂R³¹,—(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹, —alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰,—C(═O)N(R³⁰)₂, —N(R³⁰)₂, —N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂,—N(R³⁰)C(═O)OR³¹, —N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰,—OC(═O)N(R³⁰)₂, —SO₂N(R³⁰)₂, and —SO₂(R³¹), or alternatively two R²⁰moieties are linked together to form a five or six membered aryl,cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring whereinsaid five or six membered aryl, cycloalkyl, heterocyclyl,heterocyclenyl, or heteroaryl ring is R³, R⁵, and R⁶ are independentlyselected from the group consisting of —H, alkyl, haloalkyl, amino,aminoalkyl, alkoxy, CF₃, alkyl, halogen, or hydroxyl;

R⁷ and R⁸ are independently selected from the group consisting of H andalkyl, or R⁷ and R⁸ taken together with the carbon atom to which theyare shown attached is ═O;

R¹⁰ and R¹¹ are independently selected from the group consisting of H,alkyl, —N(R³⁰)₂, halogen, or hydroxyl or wherein two R¹⁰ or R¹¹moietiestogether on the same carbon atom form ═O;

R¹² is selected from the group consisting of H, alkyl, haloalkyl, andCF₃;

Y is selected from the group consisting of —(CR¹³R¹³)—, —CHR¹³C(═O)—,—(CHR¹³)O—, —(CHR¹³)N(R³⁰)—, —C(═O)—, CH-heteroaryl-, —(CHR¹³)C(═O)— and—(CHR¹³)_(r)N(H)C(═O)—.

the R¹³ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, cycloalkyl,alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl,—C(═O)R³⁰, —C(═O)N(R³⁰)₂, —(CHR³⁰)_(q)OR³¹, —(CHR³⁰)_(q)OR³¹, and—(CH²)_(q)(═O)NHR³¹;

the R³⁰ and R³¹ moieties can be the same or different, each beingindependently selected from the group consisting of H, alkyl, alkylaryl,aryl, aralkyl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl,

D is a three to nine membered cycloalkyl, three to nine memberedcycloalkenyl; or a five to eight membered aryl, heteroaryl,heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independentlyselected from N, O, S or, SO₂, wherein ring D is unsubstituted oroptionally substituted with 1-5 independently selected R²⁰ moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, -alkylamino, -alkylthiocarboxy, alkylheteroaryl, alkylthio,alkylsulfinyl-, —C(═O)—O-alkyl, amidinyl, aralkyl, aralkenyl, aralkoxy,aralkoxycarbonyl, aralkylthio, aryl, cyano, cycloalkyl, cycloalkenyl,guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl,heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro,trifluoromethoxy, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂,—(CH₂)_(q)NHR³¹, —(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —C(═NR³⁰)NHR³⁰,—C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂, —C(═O)OR³⁰, —N(R³⁰)₂,—N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹), —N(R³⁰)C(═O)N(R³⁰)₂,—N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, —SR³⁰,—SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹), and —OSi(R³⁰)₃, or alternatively twoR²⁰ moieties are linked together to form a five or six membered aryl,cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring whereinsaid five or six membered aryl, cycloalkyl, heterocyclyl,heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ringis optionally substituted with 0-4 R²¹ moieties; and

m and n are independently an integer from 1 to 4.

In another embodiment, in formula 1,

Z is N;

G is

X is N;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, alkyl, andcycloalkyl, or alternatively when X is N, the N taken together with theR¹ and R² forms a cycloalkyl or a heterocyclyl;

R³, R⁵, and R⁶ are independently selected from the group consisting of—H, alkyl, haloalkyl, amino, aminoalkyl, alkoxy, CF₃, halogen, andhydroxyl;

R⁷ and R⁸ taken together with the carbon atom to which they are shownattached is ═O,

R¹⁰, R¹¹ are independently selected from the group consisting of H,alkyl) —N(R³⁰)₂, halogen, or hydroxyl or wherein two R¹⁰ or R¹¹ moietiestogether on the same carbon atom form ═O;

R¹² is selected from the group consisting of H, alkyl, haloalkyl, andCF₃;

Y is selected from the group consisting of —(CR¹³R¹³)—, —CHR¹³C(═O)— or—C(═O)—;

the R¹³ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkylaryl, cycloalkyl,alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, or spiroalkyl;

the R³⁰ and R³¹ moieties can be the same or different, each beingindependently selected from the group consisting of H, alkyl, alkylaryl,aryl, aralkyl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

D is a phenyl or a five to eight membered aryl, heteroaryl,heterocyclenyl or a heterocyclyl ring having 0-4 heteroatomsindependently selected from N, O, S or, SO₂, wherein ring D isunsubstituted or optionally substituted with 1-5 independently selectedR²⁰ moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkylaryl,alkynyl, -alkylamino, -alkylthiocarboxy, alkylheteroaryl, alkylthio,alkylsulfinyl-, —C(═O)—O-alkyl, amidinyl, aralkyl, aralkenyl, aralkoxy,aralkoxycarbonyl, aralkylthio, aryl, cyano, cycloalkyl, cycloalkenyl,guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl,heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro,trifluoromethoxy, —(CH₂)_(q)OH, —(CH₂)_(q)OR³¹, —(CH₂)_(q)NH₂,—(CH₂)_(q)NHR³¹, —(CH₂)_(q)N(R³¹)₂, —(CH₂)_(q)C(═O)NHR³¹,—(CH₂)_(q)SO₂R³¹, —(CH₂)_(q)NHSO₂R³¹, —(CH₂)_(q)SO₂NHR³¹,-alkynylC(R³¹)₂OR³¹, —C(═O)R³⁰, —C(═O)N(R³⁰)₂, —C(═NR³⁰)NHR³⁰,—C(═NOH)N(R³⁰)₂, —C(═NOR³¹)N(R³⁰)₂, —C(═O)OR³⁰, —N(R³⁰)₂,—N(R³⁰)C(═O)R³¹, —NHC(═O)N(R³⁰)₂, —N(R³⁰)C(═O)OR³¹,—N(R³⁰)C(═NCN)N(R³⁰)₂, —N(R³⁰)C(═O)N(R³⁰)SO₂(R³¹), —N(R³⁰)C(═O)N(R³⁰)₂,—N(R³⁰)SO₂(R³¹), —N(R³⁰)S(O)₂N(R³⁰)₂, —OR³⁰, —OC(═O)N(R³⁰)₂, —SR³⁰,—SO₂N(R³⁰)₂, —SO₂(R³¹), —OSO₂(R³¹) and —OSi(R³⁰)₃, or alternatively twoR²⁰ moieties are linked together to form a five or six membered aryl;cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring whereinsaid five or six membered aryl, cycloalkyl, heterocyclyl,heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ringis optionally substituted with 0-4 R²¹ moieties; and

m and n are independently an integer from 1 to 4.

In another embodiment, in formula 1,

Z is N;

G is

X is N;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, alkyl, andcycloalkyl, or alternatively when X is N, the N taken together with theR¹ and R² forms a cycloalkyl or a heterocyclyl;

R³, R⁵, and R⁶ are independently selected from the group consisting of—H, alkyl, haloalkyl, amino, aminoalkyl, alkoxy, CF₃, halogen, andhydroxyl;

R⁷ and R⁸ taken together with the carbon atom to which they are shownattached is ═O;

R¹⁰, R¹¹ are independently selected from the group consisting of H,alkyl, amino, amino alkyl, halogen, or hydroxyl or wherein two R¹⁰ orR¹¹ moieties together on the same carbon atom form ═O;

R¹² is selected from the group consisting of H, alkyl, haloalkyl, andCF₃;

Y is selected from the group consisting of —(CR¹³R¹³)—, —CHR¹³C(═O)— or—C(═O)—;

the R¹³ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkoxy or cycloalkyl.

D is a phenyl or a five to eight membered aryl, heteroaryl,heterocyclenyl or a heterocyclyl ring having 0-4 heteroatomsindependently selected from N, O, S or, SO₂, wherein ring D isunsubstituted or optionally substituted with 1-5 independently selectedR²⁰ Moieties;

the R²⁰ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, alkenyl, alkoxy,cycloalkyl, cycloalkenyl, amino, aminoalkyl, aminocarboxyalkyl,aminosulfonylalkyl, carboxylaminoalkyl, acetyl, cyano, halogen,haloalkyl, hydroxyl, heterocyclyl, hydroxyalkyl, sulfonylmethyl,sulfonylamino, trifluoromethoxyl, or alternatively two R²⁰ moieties arelinked together to form a five or six membered aryl, cycloalkyl,heterocyclyl, heterocyclenyl, or heteroaryl ring; and

m and n are independently an integer from 1 to 4.

In another embodiment, in formula 1,

Z is N;

G is

X is N or O;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,cyclopropyl and alkyl;

R³, R⁵, R⁶ is independently selected from the group consisting of H,—CH₃, —F, —Cl, —OH, —OCH₃, —OCF₃, NH₂, SO₂CH₃, and —CF₃;

R⁷ and R⁸ are both H, or R⁷ and R⁸ taken together with the carbon atomto which they are shown attached is ═O;

R¹⁰ is selected from the group consisting of —CH₃, —CH₂CH₃, andhydroxyl, or two R¹⁰ moieties together on the same carbon atom form ═O,and m is 1-2;

R¹¹ is selected from the group consisting of H and hydroxyl or two R¹¹moieties together on the same carbon atom form ═O, and n is 1;

R¹² is selected from the group consisting of H and CF₃;

Y is selected from the group consisting of —CH₂— and —C(═O)—, and

D is a phenyl, or a 6 membered heteroaryl having 0-2 heteroatomsindependently selected from N, O, S or, SO₂ wherein ring D issubstituted with 1-2 moieties selected independently from the groupconsisting of —Cl, —CH₃, —C(═O)CH₃, —C(═O)NH₂, —F, —OH, OCH₃, OCF₃, NH₂,NH(CH₃)₂, NHSO₂CH₃, SO₂CH₃, SO₂NH₂, and trifluoromethyl.

In another embodiment, in formula 1,

Z is N;

G is

X is N or O;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,cyclopropyl and alkyl;

R³, R⁵, R⁶ is independently selected from the group consisting of H,—CH₃, —F, —Cl, —OH, —OCH₃, —OCF₃, NH₂, SO₂CH₃, and —CF₃;

R⁷ and R⁸ are both H, or R⁷ and R⁸ taken together with the carbon atomto which they are shown attached is ═O;

R¹⁰ is selected from the group consisting of —CH₃, —CH₂CH₃, andhydroxyl, or two R¹⁰ moieties together on the same carbon atom form ═O,and m is 1-2;

R¹¹ is selected from the group consisting of H and hydroxyl or two R¹¹moieties together on the same carbon atom form ═O, and n is 1;

R¹² is selected from the group consisting of H and CF₃;

Y is selected from the group consisting of —CH₂— and —C(═O)—; and

D is a phenyl, or a 6 membered heteroaryl having 0-2 heteroatomsindependently selected from N, O, S or, SO₂ wherein ring D issubstituted with 1-2 moieties selected independently from the groupconsisting of —Cl, —CH₃, —C(═O)CH₃, —C(═O)NH₂, —F, —OH, OCH₃, OCF₃, NH₂,NH(CH₃)₂, NHSO₂CH₃, SO₂CH₃, SO₂NH₂, and trifluoromethyl.

In another embodiment, in formula 1:

Z is N or NO;

G is —C≡N, or

X is N or O;

R¹ and R² are independently absent or present, and if present each isindependently selected from the group consisting of H, —CH₃, —CH₂CH₃,cyclopropyl and alkyl;

R³, R⁵, R⁶ is independently selected from the group consisting of H,—CH₃, —F, —Cl, —OH, —OCH₃, —OCF₃, SO₂CH₃, and —CF₃;

R⁷ and R⁸ are both H, or R⁷ and R⁸ taken together with the carbon atomto which they are shown attached is ═O;

R¹⁰ is selected from the group consisting of —CH₃, —CH₂CH₃, andhydroxyl, or two R¹⁰ moieties together on the same carbon atom form ═O,and m is 1-2;

R¹¹ is selected from the group consisting of H and hydroxyl or two R¹¹moieties together on the same carbon atom form ═O, and n is 1;

R¹² is selected from the group consisting of H and CF₃;

Y is selected from the group consisting of —CH₂— and —C(═O)—; and

D is a phenyl, or a 6 membered heteroaryl having 0-2 heteroatomsindependently selected from N, O, S or, SO₂ wherein ring D issubstituted with 1-2 moieties selected independently from the groupconsisting of —Cl, —CH₃, —F, —OH, NH₂, SO₂CH₃, and trifluoromethoxy.

In another embodiment, the compound of formula 1 is in optically pureform.

In another embodiment, the compound of formula 1 is selected from thegroup consisting of

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

In yet another aspect, the compound of Formula 1 can be in purifiedform.

In another embodiment, the pharmaceutical composition comprising atleast one compound of Formula 1, or a pharmaceutically acceptable salt,solvate or ester thereof in combination with at least onepharmaceutically acceptable carrier, further comprises at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating a CXCR3 chemokine receptor mediated disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts). Thus, for non-limiting illustration purposes, acompound of Formula III and an additional therapeutic agent may bepresent in fixed amounts (dosage amounts) in a single dosage unit (e.g.,a capsule, a tablet and the like). A commercial example of such singledosage unit containing fixed amounts of two different active compoundsis VYTORIN® (available from Merck Schering-Plough Pharmaceuticals,Kenilworth, N.J.).

In yet another embodiment, the present invention discloses methods forpreparing pharmaceutical compositions comprising the inventiveheterocyclic substituted piperazine compounds of Formula 1 as an activeingredient. In the pharmaceutical compositions and methods of thepresent invention, the active ingredients will typically be administeredin admixture with suitable carrier materials suitably selected withrespect to the intended form of administration, i.e. oral tablets,capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition. Suitable bindersinclude starch, gelatin, natural sugars, corn sweeteners, natural andsynthetic gums such as acacia, sodium alginate, carboxymethylcellulose,polyethylene glycol and waxes. Among the lubricants there may bementioned for use in these dosage forms, boric acid, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrants includestarch, methylcellulose, guar gum and the like. Sweetening and flavoringagents and preservatives may also be included where appropriate. Some ofthe terms noted above, namely disintegrants, diluents, lubricants,binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. anti-inflammatory activity andthe like. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and pacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 1.0 milligramto about 1,000 milligrams, preferably from about 1.0 to about 950milligrams, more preferably from about 1.0 to about 500 milligrams, andtypically from about 1 to about 250 milligrams, according to theparticular application. The actual dosage employed may be varieddepending upon the patient's age, sex, weight and severity of thecondition being treated. Such techniques are well known to those skilledin the art.

Generally, the human oral dosage form containing the active ingredientscan be administered 1 or 2 times per day. The amount and frequency ofthe administration will be regulated according to the judgment of theattending clinician. A generally recommended daily dosage regimen fororal administration may range from about 1.0 milligram to about 1,000milligrams per day, in single or divided doses.

Some useful terms are described below:

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gels—refers to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powders for constitution—refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato, and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

Disintegrants—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

Binders—refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d′l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glidents—materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients Gan include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability—refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control. Conventional methods for preparing tablets are known. Suchmethods include dry methods such as direct compression and compressionof granulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

It will be apparent to those skilled in the art that many modifications,variations and alterations to the present disclosure, both to materialsand methods, may be practiced. Such modifications, variations andalterations are intended to be within the spirit and scope of thepresent invention.

As stated earlier, the invention includes tautomers, enantiomers andother stereoisomers of the compounds also. Thus, as one skilled in theart knows, certain imidazole compounds may exist in tautomeric forms.Such variations are contemplated to be within the scope of theinvention. Certain compounds of the present invention may exist inmultiple crystalline forms or amorphous forms. All physical forms of thecurrent invention are contemplated.

Compounds of this invention which contain unnatural proportions ofatomic isotopes (i.e. “radiolabeled compounds”) whether their use istherapeutic, diagnostic or as a research reagent are contemplated underthis invention,

Another embodiment of the invention provides a pharmaceuticalcomposition which in addition to comprising at least one compound offormula 1, or a pharmaceutically acceptable carrier as set forth abovefurther comprises at least one additional agent, drug, medicament,antibody and/or inhibitor for treating a CXCR3 chemokine receptormediated disease.

In another embodiment, the CXCR3 chemokine receptor mediated disease ofthis invention is an inflammatory or immune disease, said inflammatoryor immune disease selected from the group consisting of:neurodegenerative disease, multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriaticarthritis, juvenile rheumatoid arthritis, atherosclerosis, vasculitis,chronic heart failure, cerebrovascular ischemia, encephalitis,meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis,eczema, urticaria, type I diabetes, asthma, conjunctivitis, ophthalmicinflammation, otitis, allergic rhinitis, chronic obstructive pulmonarydisease, sinusitis, dermatitis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, Behcet's syndrome, pulmonary fibrosis,endometriosis, gout, cancer, cachexia, a viral infection, a bacterialinfection, an organ transplant condition, a skin transplant condition,and a graft versus host disease.

In another embodiment, the neurodegenerative disease of this inventionis Alzheimer's disease.

In another embodiment, the present invention discloses a method fortreating a CXCR3 chemokine receptor mediated disease in a patient inneed of such treatment comprising administering to the patient (a) aneffective amount of at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one additional agent, drug,medicament, antibody and/or inhibitor for treating a CXCR3 chemokinereceptor mediated disease, in combination with a pharmaceuticallyacceptable carrier.

In another embodiment, at least one compound of Formula 1 binds to aCXCR3 receptor.

In another embodiment, the invention provides methods of preparingcompounds of Formula 1, as well as methods for treating diseases, forexample, treatment (e.g., palliative therapy, curative therapy,prophylactic therapy) of certain diseases and conditions e.g.,inflammatory diseases (e.g., psoriasis, inflammatory bowel disease),autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis),graft rejection (e.g., allograft rejection, xenograft rejection),ophthalmic inflammation or dry eye, infectious diseases as well ascancers and tumors, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses, ophthalmic inflammation or dry eye, type Idiabetes, viral meningitis and tuberculoid leprosy, comprisingadministering a therapeutically effective amount of a compound ofFormula 1 or a pharmaceutically acceptable salt, solvate or esterthereof.

In another embodiment, the present invention provides a method fortreating a CXCR3 chemokine receptor mediated disease comprisingadministering: (a) a therapeutically effective amount of at least onecompound according to Formula 1, or a pharmaceutically acceptable salt,solvate or ester thereof concurrently or sequentially with (b) at leastone medicament selected from the group consisting of: disease modifyingantirheumatic drugs; nonsteroidal anti-inflammatory drugs; COX-2selective inhibitors; COX-1 inhibitors; immunosuppressives (such ascyclosporins and methotrexate); steroids (including corticosteroids suchas glucorticoids); PDE IV inhibitors, anti-TNF-α compounds,TNF-α-convertase (TACE) inhibitors, MMP inhibitors, cytokine inhibitors,glucocorticoids, corticosteroids, other chemokine inhibitors (such asCCR2 and CCR5), CB2-selective inhibitors, p38 inhibitors, biologicalresponse modifiers, anti-inflammatory agents and therapeutics.

In another embodiment, the present invention provides a method oftreating inflammatory bowel disease in a patient in need of suchtreatment comprising administering to the patient a therapeuticallyeffective amount of: (a) at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: sulfasalazine, 5-aminosalicylic acid, sulfapyridine,anti-TNF compounds, anti-IL-1 2 compounds, corticosteroids,glucocorticoids, T-cell receptor directed therapies (such as anti-CD3antibodies), immunosuppresives, methotrexate, azathioprine, and6-mercaptopurines.

In another embodiment, the present invention provides a method oftreating graft rejection in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of: (a) at least one compound of Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one compound selected from the group consisting of:cyclosporine A, FK-506, FTY720, beta-interferon, rapamycin,mycophenolate, prednisolone, azathioprine, cyclophosphamide and anantilymphocyte globulin.

In another embodiment, the present invention provides a method oftreating multiple sclerosis in a patient in need of such treatment themethod comprising administering to the patient a therapeuticallyeffective amount of: (a) a therapeutically effective amount of at leastone compound of Formula 1, or a pharmaceutically acceptable salt,solvate or ester thereof concurrently or sequentially with (b) at leastone compound selected from the group consisting of: beta-interferon,glatiramer acetate, corticosteroids, glucocorticoids, methotrexate,azothioprine, mitoxantrone, VLA-4 inhibitors, FTY720, anti-IL-12inhibitors, and CB2-selective inhibitors.

In another embodiment, the present invention provides a method oftreating multiple sclerosis in a patient in need of such treatment themethod comprising administering to the patient a therapeuticallyeffective amount of: (a) a therapeutically effective amount of at leastone compound of Formula 1, or a pharmaceutically acceptable salt,solvate or ester thereof concurrently or sequentially with (b) at leastone compound selected from the group consisting of: methotrexate,cyclosporin, leflunomide, sulfasalazine, corticosteroids, β-methasone,β-interferon, glatiramer acetate, prednisone, etonercept, andinfliximab.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis in a patient in need of such treatment themethod comprising administering to the patient a therapeuticallyeffective amount of: (a) at least one compound of Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: non-steroidal anti-inflammatory agents, COX-2 inhibitors,COX-1 inhibitors, immunosuppressives, cyclosporine, methotrexate,steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors,corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selectiveinhibitors, caspase (ICE) inhibitors and other classes of compoundsindicated for the treatment of rheumatoid arthritis.

In another embodiment, the present invention provides a method oftreating psoriasis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: a) at least one compound of Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one compound selected from the group consisting of:immunosuppressives, cyclosporins, methotrexate, steroids,corticosteroids, anti-TNF-α compounds, anti-IL compounds, anti-IL-23compounds, vitamin A and D compounds and fumarates.

In another embodiment, the present invention provides a method oftreating ophthalmic inflammation (including, for e.g., uveitis,posterior segment intraocular inflammation, Sjogren's syndrome) or dryeye in a patient in need of such treatment the method comprisingadministering to the patient a therapeutically effective amount of: a)at least one compound according to Formula 1, or a pharmaceuticallyacceptable salt, solvate or ester thereof concurrently or sequentiallywith (b) at least one compound selected from the group consisting of:immunosuppressives, cyclosporins, methotrexate, FK506, steroids,corticosteroids, and anti-TNF-α compounds.

The invention also provides a method of treating an inflammatory orimmune disease, said disease selected from the group consisting of:neurodegenerative disease, multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriaticarthritis, juvenile rheumatoid arthritis, atherosclerosis, vasculitis,chronic heart failure, cerebrovascular ischemia, encephalitis,meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis,eczema, urticaria, type I diabetes, asthma, conjunctivitis, ophthalmicinflammation, otitis, allergic rhinitis, chronic obstructive pulmonarydisease, sinusitis, dermatitis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, Behcet's syndrome, pulmonary fibrosis,endometriosis, gout, cancer, cachexia, a viral infection, a bacterialinfection, an organ transplant condition, a skin transplant condition,and a graft versus host disease in a patient in need of such treatment,said method comprising administering to the patient an effective amountof (a) at least one compound according to Formula 1, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one medicament selected from the groupconsisting of: disease modifying antirheumatic drugs; nonsteroidalantiinflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors;immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-α compounds,TNF-alpha-convertase inhibitors, cytokine inhibitors, MMP inhibitors,corticosteroids, glucocorticoids, chemokine inhibitors, CB2-selectiveinhibitors, biological response modifiers; anti-inflammatory agents andtherapeutics.

Some specific compounds of the present invention are shown in Table 1below, along with their IC₅₀ ratings. The IC₅₀ values are rated, “A” forICO₅₀ values less than about 25 nanomolar (nM), “B” for IC₅₀ values inthe range of from about 25 to about 100 nM and “C” for IC50 valuesgreater than about 100 nM. For example, Compound No. 107 has an IC₅₀ of0.2 nM.

TABLE 1 Compound Number STRUCTURE Ki 1

A 2

A 3

A 4

A 5

A 6

A 7

A 8

A 9

A 10

A 11

B 12

C 13

C 14

C

Unless otherwise stated, the following abbreviations have the statedmeanings in the Examples below:

-   BINAP=racemic-2,2′-bis(diphenylphosphino)-1,1 ′-binaphthyl-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   DBN=1,5-diazabicyclo[4.3.0]non-5-ene-   EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   HATU=N-(Diethylamino)-1H-1,2,3-triazolo[4,5-b-pyridine-1-ymethylene]-N-methylmethanaminium    Hexafluorophosphate N-oxide-   HOBT=1-hydroxybenzotriazole-   DCCG dicyclohexylcarbodiimide-   Dibal-H-=diisobutylaluminum hydride-   DBPD=2-(Di4-butylphosphinobiphenyl-   DMF=dimethylformamide-   DCM=dichloromethane-   LAH=lithium aluminum hydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   NaBH₄=sodium borohydride-   NaBH₃CN=sodium cyanoborohydride-   LDA=lithium diusopropylamide-   p-TsOH=p-toluenesulfonic acid-   p-TsCl=p-toluenesulfonyl chloride-   PPTS=pyridinium p-toluenesulfonate-   m-CPBA=m-Chloroperbenzoic acid-   TMAD-N,N,N′,N′-tetramethylazodicarboxamide-   CSA=camphorsulfonic acid-   NaHMDS=sodium hexamethyl disilylazide-   HRMS=High Resolution Mass Spectrometry-   HPLC=High Performance Liquid Chromatography-   LRMS=Low Resolution Mass Spectrometry-   nM=nanomolar-   Ki=Dissociation Constant for substrate/receptor complex-   pA2=−logEC₅₀, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol,    294, 329-335.-   Ci/mmol=Curie/mmol (a measure of specific activity)-   Tr=Triphenylmethyl-   Tris=Tris (hydroxymethyl)aminomethane-   THF=Tetrahydrofuran-   TFA=Trifluoroacetic acid

GENERAL SYNTHESIS

Compounds of the present invention can be prepared by a number ofmethods evident to one skilled in the art. Preferred methods include,but are not limited to, the general synthetic procedures describedherein. One skilled in the art will recognize that one route will beoptimal depending on the choice of appendage substituents. Additionally,one skilled in the art will recognize that in some cases the order ofsteps may be varied to avoid functional group incompatibilities. Oneskilled in the art will recognize that a more convergent route (i.e.non-linear or preassembly of certain portions of the molecule) is a moreefficient method of assembly of the target compounds. Methods for thepreparation of compounds of Formula 1 were variables [R¹,R³, R⁵, R⁶, R⁷,R⁸, R¹⁰, R¹¹, R¹², R²⁰, R²¹, A, E, L, Q, X, Y, Z, m, n, o, w and p] areas defined above, are shown in Schemes 1-4. EN is described below andPr¹, Pr², Pr³ and Pr⁵ are protecting groups exemplified below.

The thus prepared compounds may be analyzed for their composition andpurity as well as characterized by standard analytical techniques suchas, for example, elemental analysis, NMR, mass spectroscopy, and IRspectra.

The starting material and reagents used in preparing compounds describedare either available from commercial suppliers such as Aldrich ChemicalCo. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or wereprepared by literature methods known to those skilled in the art.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the need for the protection of certain functionalgroups (i.e. derivatization for the purpose of chemical compatibilitywith a particular reaction condition). Suitable protecting groups forcarboxylic acids include methyl, ethyl, isopropyl, or benzyl ester andthe like. Suitable protecting groups for an amine (Pr² or Pr³) includemethyl, benzyl, ethoxyethyl, t-butoxycarbonyl, phthaloyl and the like.All protecting groups can be appended to and removed by literaturemethods known to those skilled in the art.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the construction of an amide bond. Methods includebut are not limited to the use of a reactive carboxy derivative (e.g.acid halide, or ester at elevated temperatures) or the use of an acidwith a coupling reagent (e.g. DECI, DCC) with an amine at 0° C. to 100°C. Suitable solvents for the reaction are halogenated hydrocarbons,ethereal solvents, dimethylformamide and the like. The reaction may beconducted under pressure or in a sealed vessel.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the construction of an amine bond. One such methodis but not limited to the reaction of a primary or secondary amine witha reactive carbonyl (e.g. aldehyde or ketone) under reductive aminationconditions. Suitable reducing reagents of the intermediate imine aresodium borohydride, sodium triacetoxyborohydride and the like at 0° C.to 100° C. Suitable solvents for the reaction are halogenatedhydrocarbons, ethereal solvents, dimethylformamide and the like. Anothersuch method is but not limited to the reaction of a primary or secondaryamine with a reactive alkylating agent such as an alkyl halide, benzylhalide, mesylate, tosylate or the like. Suitable solvents for thereaction are halogenated hydrocarbons, ethereal solvents,dimethylformamide and the like. The reaction may be conducted underpressure or in a sealed vessel at 0° C. to 100° C.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the reduction of a reducible functional group.Suitable reducing reagents include sodium borohydride, lithium aluminumhydride, diborane and the like at −20° C. to 100° C. Suitable solventsfor the reaction are halogenated hydrocarbons, ethereal solvents,dimethylformamide and the like.

One skilled in the art will recognize that the synthesis of compounds ofFormula 1 may require the oxidation of a functional group. Suitableoxidizing reagents include oxygen, hydrogen peroxide,m-chloroperoxybenzoic acid and the like at −20° C. to 100° C. Suitablesolvents for the reaction are halogenated hydrocarbons, etherealsolvents, water and the like.

The starting materials and the intermediates of a reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials can be characterized usingconventional means, including physical constants and spectral data.

General Description

Step A. Amination of a Pyridine Ring

A suitably protected 2-halo pyridine or phenyl of structure I is reactedwith a piperazine of structure II to form a compound of generalstructure III. Preferably the reaction is carried out in a solvent suchas dioxane or DMF in the presence of a base such as potassium carbonateor cesium carbonate with or without the assistance of a catalyst such aspalladium acetate. Alternatively, other leaving groups may replace thechlorine (O-mesyl, Br etc.) or a group capable of activation under thereaction conditions (H, OH, etc.) may be used.

Alternatively, a compound of structure I can be reacted with a compoundof structure XII to form a compound of structure VIII.

Step B.

Optionally, if the product of step A is a protected piperazine ofstructure III, deprotection is required. When Pr² is benzyl orsubstituted benzyl, deprotection can be effected by reaction under apressure of hydrogen gas in the presence of a catalyst such aspalladium. When Pr² is ethoxyethyl deprotection can be effected byreaction with trimethylsilyl iodide. When Pr² is t-butoxycarbonyldeprotection can be effected with a strong acid such as trifluoroaceticacid, hydrogen chloride, p-toluenesulfonic acid.

Step C.

A piperazine of structure IV is reacted with a ketone of structure V inthe presence of a reducing agent to form a compound of structure VIwhere R¹² is hydrogen. General conditions for the reductive aminationreaction are described above.

In certain cases Pr³ represents an appropriately substitutedpiperidone-Y-ring D residue.

Step C′ (when R¹²═CN)

A piperazine of structure IV is reacted with a ketone of structure V inthe presence of a reducing agent to form a compound of structure VIwhere R¹² is a cyanide residue. Typical conditions are the reaction ofan equi-molar quantity of a piperazine of structure IV and a ketone ofstructure in the presence of titanium isopropoxide in a halogenatedsolvent such as methylene chloride for 1-48 hours. Subsequent additionof a cyanide source such as dimethylaluminum cyanide affords a compoundof structure VI where R¹² is a cyanide residue.

Step D

A protected piperidine of structure VI or structure X is deprotected toprovide the secondary amine of structure VII or structure XI. When Pr²is benzyl or substituted benzyl deprotection can be effected by reactionunder a pressure of hydrogen gas in the presence of a catalyst such aspalladium. When Pr² is ethoxyethyl deprotection can be effected byreaction with trimethylsilyl iodide. When Pr² is t-butoxycarbonyldeprotection can be effected with a strong acid such as trifluoroaceticacid.

Step D′

Optionally, functional group introduction or manipulation can beperformed as required. A compound of structure VI or structure X, whenR³=Cl or Br is reacted with a organometallic alkylating agent such aalkylboronic acid, or an alkyl halide in the presence of a metal topromote heterocoupling, or nucleophile to yield a different structure ofgeneral structure VII or structure XI where the halogen at the R³position has been replaced by the appropriate group described for R³.

Step E

A secondary piperidine of structure VII or XI is functionalized withring D by methods such as alkylation or acylation to provide compoundsof structure VIII or IX. General methods for such alkyations andacylations are described above and are well known to those skilled inthe art.

Step F

Step F′

Optionally, functional group manipulation of a compound of structure IXmay be done to provide additional related compounds of structure IX.

Compounds of structure IX can be prepared by the general methodsoutlined in scheme 1. Synthesis of the specifically exemplifiedcompounds, were prepared as described in detailed below. The followingEXAMPLES are being provided to further illustrate the present invention.They are for illustrative purposes only; the scope of the invention isnot to be considered limited in any way thereby.

The following examples are intended to illustrate, but not to limit, thescope of the invention.

EXAMPLE 1

To a cooled (−78° C.) 1000 ml RB flask containing 200 ml of methanol wasadded thionyl chloride (10 ml, 140 mmol) dropwise followed by5-bromopicolinic acid (15 g, 75 mmol). After stirring 10 min at −78° C.,the reaction was allowed to warm to rt and stirred for 16 hr. Excessthionyl chloride and methanol were removed in vacuo to yield A2 (18 g,95%) as a light brown solid. M+H=216

EXAMPLE 2

A 250 ml round bottom flask was charged with A2 (4 g, 15.9 mmol),1-Boc-2-S-ethyl piperazine A3 (prepared as per Kiley et al Org. Prep.Proc. Int. 1990, 22, 761; 4.2 g, 18.6 mmol),tris(dibenzylideneacetone)dipalladium, (340 mg, 0.37 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (495 mg,0.74 mmol), cesium carbonate (12g, 37.2 mmol) and toluene (80 ml). Afterthe mixture was heated at 100° C. for 16 h, freshtris(dibenzylidene-acetone)dipalladium (340 mg, 0.37 mmol) and BINAP(495 mg, 0.74 mmol) were added and the heating was continued for 3 days.The solvent was removed in vacuo, and the residue was suspended in a 100ml portion of ethyl acetate. This mixture was extracted with water andbrine, dried over sodium sulfate, and concentrated in vacuo.Purification of the residue via silica gel flash chromatography (5%methanol/95% DCM) yielded 5.3 g of a partially purified material whichwas used directly in the next step. M+H=350

EXAMPLE 3

Intermediate A4 (5.28 g, 15.1 mmol) was stirred with N-bromo-succinimide(5.4 g, 30.2 mmol) in 30 ml DMF for 24 h at rt. The solvent was removedin vacuo and the residue was directly purified via flash silica gelchromatography eluted with 50% ethyl acetate/50% hexanes to yield A5(1.22 g, 19% yield, M+H=428) Further elution of the column with 10% 7Nammonia in methanol/90% DCM yielded A6 (1 28 g, 25%, M+H=328).

EXAMPLE 4

Intermediate A5 (1.22 g 2.8 mmol), was deprotected by stirring in amixture of TFA (25 ml) and DCM (75 ml) for 30 min followed by removal ofthe TFA and DCM in vacuo. The resultant residue was combined withpreviously purified A6 (see above, 1.28 g, 3.9 mmol) in dichloroethane(20 ml) and triethylamine (0.42 ml, 3 mmol) was added. To this solutionof A6 (6.75 mmol total) was added sodium triacetoxyborohydride (2.85 g,13.5 mmol) and 1-Boc-4-piperidone (2.67 g, 13.5 mmol). After stirring atrt for 16 h, OCM (50 ml) was added and the mixture was extracted withsaturated sodium bicarbonate and brine, dried over sodium sulfate, andthe solvent was removed in vacuo. The resultant residue was purified byflash silica gel chromatography to yield A7 (1.89 g, M+H=512). Althoughcontaminated with Boc-piperinol, this material was used directly in thesubsequent step.

EXAMPLE 5

Intermediate A7 (1.89 g, 3.7 mmol) was combined with methylboronic acid(666 mg, 11.1 mmol), potassium carbonate (2.4g, 17.6 mmol), andtrans-dichiorobis(triphenylphosphine)palladium (II) (260 mg, 0.37 mmol)in anhydrous DMF (10ml) and heated to 90° C. for 16 h. The solvent wasremoved in vacuo and the resultant residue was taken up in ethyl acetate(50 ml) and extracted with saturated sodium bicarbonate and brine. Theorganic layer was dried over sodium sulfate, concentrated in vacuo, andpurified by silica gel flash chromatography eluted with 5% methanol/95%DCM to yield intermediate A8 (960 mg, 20% yield). M+H=447

EXAMPLE 6

The Boc protecting group of intermediate A8 (960 mg, 2.16 mmol) wasremoved by stirring with 10 ml TFA in 20 ml DCM for 45 min. Removal ofthe solvent yielded the deprotected TFA salt A9. An aliquot of A9 (0.86mmol) was stirred with 4-chlorobenzoyl chloride (0.17 ml, 1.29 mmol) andtriethylamine (0.36 ml, 2.58 mmol) in 5 ml DCM for 16 hr. This mixturewas washed with saturated sodium bicarbonate and brine, dried oversodium sulfate, concentrated in vacuo, and purified by silica gel flashchromatography to yield A10 (85 mg, 0.18 mmol, 20%). M+H=485

Alternate Route to Intermediate 10

EXAMPLE 7

To a solution of A6 (8.4 mmol) in 20 ml dichloroethane was added sodiumtriacetoxyborohydride (3.5 g, 16.8 mmol),1-(4-chlorobenzoyl)-piperidin-4-one (3.28 g, 13.8 mmol), andtrethylamine (2.3 ml, 16.8 mmol). After stirring at rt for 16 h, DCM (50ml) was added and the mixture was extracted with saturated sodiumbicarbonate and brine, dried over sodium sulfate, and the solvent wasremoved in vacuo. The resultant residue was purified by flash silica gelchromatography to yield A11 (3.2 g, M+H=549). Although contaminated withBoc-piperinol, this material was used directly in subsequent step.

EXAMPLE 8

Intermediate A11 (3.2 g, 5.8 mmol) was combined with methylboronic acid(1.0 g, 17.4 mmol), potassium carbonate (3.8 g, 4.75 mmol), andtrans-dichlorobis(triphenylphosphine)palladium (II) (405 mg, 0.58 mmol)in anhydrous DMF (25 ml) and heated to 90° C. for 16 h. DMF was removedin vacuo and the residue was extracted between ethyl acetate andsaturated sodium bicarbonate. The organic layer was washed with brine,dried over sodium sulfate, concentrated in vacuo, and purified by silicagel flash chromatography to yield compound A10 (1.1 g, 39%).

EXAMPLE 9

A screw top 50 ml vessel was charged with A10 (0.075 g, 0.15 mmole), 10ml dioxane, and ammonia (10 ml, 0.5 N in dioxane). The solution washeated to 80° C. overnight in a sealed vessel. The reaction was cooledand concentrated to a clear oil. Purification on silica get affordedcompound No. 10 in 70% yield as a semi-solid. M+H=471

EXAMPLE 10

A screw top 50 ml vessel was charged with A10 (0.075 g, 0.15 mmole), 10ml dioxane, and Cyclopropylamine (0.1 g, 1.75 mmol). The solution washeated to 80° C. overnight in a sealed vessel. The reaction was cooledand concentrated to a clear oil. Purification on silica gel affordedcompound No. 6 in 70% yield as a semi-solid. M+H=511

EXAMPLE 11

An aliquot of A9 (0.65 mmol) was stirred with 4-chloro-3-fluorobenzoicacid (170 mg, 0.98 mmol), EDCl (250 mg, 1.3 mmol), anddiisopropyl-ethylamine (0-57 ml, 3.2mmol) in 5 ml DMF for 16 hr. Thismixture was diluted with ethyl acetate (50 ml), washed with water andbrine, dried over sodium sulfate, concentrated in vacuo, and purified bypreparative reverse phase HPLC (Sunfire™ 19×100 mm 5μ C18 columns 8 mingradient: 10%→40% acetonitile/water with 0.1% TFA) to yield A15 (140 mg,35%). M+H=503

EXAMPLE 12

A screw top 50 ml vessel was charged with A15 (0.085 g, 0.17 mmole), 10ml dioxane, and Cyclopropylamine (0.1 g, 1.75 mmol). The solution washeated to 80° C. overnight in a sealed vessel. The reaction was cooledand concentrated to a clear oil. Purification on silica gel affordedcompound No. 5 in 84% yield as a semi-solid. M+H=529

EXAMPLE 13

An aliquot of A9 (0.65 mmol) was stirred with 4-chloro-benzylbromide(113 mg, 0.7 mmol), EDCI (250 mg, 1.3 mmol), and diisopropyl-ethylamine(0.57 ml, 3.2 mmol) in 5 ml DMF for 16 hr. This mixture was diluted withethyl acetate (50 ml), washed with water and brine, dried over sodiumsulfate, concentrated in vacuo, and purified by on silica to afford A38(200 mg) M+H=471

EXAMPLE 13

Compound No. 3 was prepared with a similar procedure to example 9 above.No. 3 M+H=457

EXAMPLE 14

A screw top 25 ml vessel was charged with A38 (0.02 g, 0.04 mmole), and2 N ethylamine in methanol (1 ml, 2 mmol). The solution was heated to60° C. overnight in a sealed vessel. The reaction was cooled andconcentrated to a clear oil. Purification on silica gel affordedcompound No. 1 in 54% yield as a semi-solid. M+H=485

EXAMPLE 15

A 250 ml round bottom flask was charged with A2 (2 g, 9.4 mmol),1-Boc-2(S)-ethyl-5(R)-methylpiperazine acetic acid salt A18 (2,2 g, 9.4mmol) tris(dibenzylideneacetone)dipalladium ((172 mg, 0.19 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (250 mg,0.38 mmol), cesium carbonate (6.1 g, 18.8 mmol) and toluene (50 ml).After the mixture was heated at 100° C. for 16 h, freshtris(dibenzylideneacetone)dipalladium (0), (172 mg, 0.149 mmol) andBINAP (250 mg, 0.38 mmol) were added and the heating was continued for 3further days. The solvent was removed in vacuo, and the residue wassuspended in a 100 ml portion of ethyl acetate. This mixture wasextracted with water and brine, dried over sodium sulfate, andconcentrated in vacuo. Purification of the residue via silica gel flashchromatography column (gradient 50% ethylacetate/50% hexanes→5%methanol/195% DCM) yielded A19 (1.7 g, 50%). M+H=364

EXAMPLE 16

Compound A19 (443 mg, 1.2 mmol) and N-bromosuccinimide (280 mg, 1.6mmol) were stirred in DMF (3 ml) for 16 h at rt. DMF was removed invacuo and the residue was extracted between ethyl acetate and saturatedsodium bicarbonate. The ethyl acetate layer was washed with brine, driedover sodium sulfate, concentrated in vacuo, and purified by silica gelflash chromatography (50% ethylacetate/50% hexanes) to yield bromide A20(194 mg, 36.1%) M+H=442

EXAMPLE 17

Intermediate A20 (435 mg, 0.98 mmol), copper(I) iodide (10 mg, 0.049mmol), sodium iodide (295 mg, 1.97 mmol) andN,N′-dimethylcyclohexanediamine (16 μl, 0.098 mmol) were combined in1,4-dioxane (2 ml) and heated to 110° C. under argon for 16 h. Thesolution was allowed to cool to rt and 30% aqueous ammonia (5 ml) wasadded. The mixture was poured into water (20 ml) and extracted with DCM(3 times). The organics were dried over magnesium sulfate andconcentrated in vacuo. Purification by silica gel flash chromatography(5% methanol/95% DCM) yielded iodide A21 (319 mg, 66%). M+H=490

EXAMPLE 18

Iodide A21 (221 mg, 0.45 mmol) was dissolved in DMF (2 ml) and heated to100° C. for 16 h in the presence of Methyl chlorodifluoroacetate (96 μl,0.9 mmol), copper(I) iodide (86 mg, 0.45 mmol), and potassium fluoride(26 mg, 0.45 mmol). After removing the DMF in vacuo, the residue wasextracted between DCM (3 ml) and 10% ammonium hydroxide (3 ml). Theaqueous layer was further extracted with DCM (2×3 ml) and the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Mass spectral analysis indicated a mixture ofchlorinated (M+H=398) and trifluoromethylated (M+H=432) products. Thecrude material was treated with 4N HCl in 1,4-dioxane (5 ml) for 30minutes and the solvent was removed in vacuo to yield a mixture of A22and A23 which was directly carried to the next step.

EXAMPLE 19

The mixture of A22 and A23 was stirred at rt with1-(4-chlorobenzoyl)-piperidin-4-one (107 mg, 0.45 mmol), sodiumtriacetoxyborohydride (95 mg, 0.45 mmol) and triethylamine (0.2 ml, 1.35mmol) in 1,2-dichloroethane (3 ml) for 16 h. The reaction was quenchedwith saturated sodium bicarbonate (2 ml), extracted with DCM (3×2 ml),dried over sodium sulfate, concentrated in vacuo and purified by silicagel flash chromatography (5% methanol/95% DCM) to give a co-elutingmixture (228 mg) of chloride A24 (M+H=519) andtrifluoromethyl-substituted A25 (M+H=553).

PREPARATIVE EXAMPLE 20 Alternate Piperazine Starting Material

Step A

Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution ofD-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH₂Cl₂ (300mL). The solution was stirred at 22° C. for 19 h. The reaction mixturewas cooled with an ice-water bath and solid sodium triacetoxyborohydride(46 g, 0.22 mol) was added in portions over −15 min. The cooling bathwas removed and the milky white solution was stirred at 22° C. for 7 h.The solvent was removed by rotary evaporation under reduced pressure andthe resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl(˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). Theaqueous layer was adjusted to pH˜10 with 1 N NaOH (450 mL) and the milkyaqueous layer was extracted immediately with EtOAc (3×250 mL). Thecombined organic layers were washed with brine (˜250 mL)₁ dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure toafford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorlesssemi-solid.

Step B.

To a solution of N-benzyl-D-alanine methyl ester (28 g, 0,1 5 mol) andEDCl.HCl (30.6 g, 0.160 mmol) in CH₂Cl₂ (250 mL) was added a solution ofN-Boc-2(S)-aminobutyric acid (29.5 g, 0.145 mol; Anaspec, Inc.) inCH₂Cl₂ (100 mL). The reaction mixture was stirred at 22° C. for 16 h.Additional N-Boc-2(S)-aminobutyric acid (5.9 g, 29 mmol) and EDCl.HCl(11.1 g, 58 mmol) and DMF (20 mL) were added. After 1 day, the solventswere removed under reduced pressure, and the residue was dissolved inEtOAc. The organic solution was washed with 0.5 N aqueous HCl, saturatedaq. sodium carbonate, brine, and was then dried over anhydrous sodiumsulfate. Subsequent filtration and concentration gave a colorless oil

The oil was dissolved in CH₂Cl₂ (200 mL) and HCl gas was bubbled intothe stirred solution for 1.5 h. After removal of solvent under reducedpressure, the resulting white solid was suspended in EtOAc (500 mL) andaqueous NaHCO₃ solution (150 mL). The mixture was stirred at rt for 18h. The organic layer was separated, washed with brine, dried overanhydrous MgSO₄, filtered, and concentrated to give compound A35 (21.9g, 61% over 2 steps).

Step C.

The diketopiperazine A35 (21.9 g, 89 mmol) was dissolved in dry THF (500mL). Powdered LiAlH₄ (10.1 g, 267 mmol) was added cautiously and inportions over ˜30 min. The reaction mixture was stirred at 22° C. for 1h, at 65° C. for 1 d, and then at 22° C. for a further 24 h. Thereaction was quenched by cautious dropwise addition of water (10 mL)over 1 h. 1 N aqueous NaOH solution (20 mL) and water (30 mL) were addedsequentially and the milky white reaction mixture was stirred at rt for1 h. The white gelatinous precipitate that formed was removed byfiltration through Celite®. The filter cake was washed copiously withEtOAc (˜500 mL). The combined filtrates were evaporated. The residue wasdissolved in Et₂O (˜500 mL) and then taken to dryness to afford2(S)-ethyl-4-benzyl-5(R)-methylpiperazine (18.4 g, 93%) as a pale goldenyellow oil.

The piperazine above (18.3 g, 84 mmol) was dissolved in CH₂Cl₂ (40 mL)and solid di-t-butyl dicarbonate (18.3 g, 84 mmol) was added. Afterstirring for 30 min at rt, the solvent was removed and the resultingyellow liquid was purified by flash column chromatography, eluting with3:1 hexanes-Et₂O, to afford1-Boc-2(S)-ethyl-4-benzyl-5(R)-methylpiperazine (A36) as a clear,colorless liquid (24.9 g, 93%).

Step D,

A mixture of 1-Boc-2(S)-ethyl-4-benzyl-5(R)-methylpiperazine (A36; 13.6g, 43 mmol), glacial acetic acid (2.5 mL) and 10% Pd/C (4.5 g) inmethanol (150 mL) was shaken under H₂ atmosphere (50 psi) for 24 h. Themixture was filtered through Celite® and the filter cake was washedcopiously with EtOAc (˜500 mL). The combined filtrates were dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure toafford a clear colorless oil. Further co-evaporation with CH₂Cl₂ (200mL) and Et₂O (2×200 mL) gave the desired1-Boc-2(S)-ethyl-5(R)-methylpiperazine acetic acid salt (A37, 9.7 g) asa viscous oil.

Piperazine A37 may be used in place of piperazine or a substitutedpiperazine in the above examples.

Following Analogous Procedure for the Preparation of Compounds no. 1, 3,5, 6 and 10 above the following compounds were prepared.

NO. from table 1 MW 2 545.65 4 505.59 7 544.53 8 511.62 9 542.10 11578.08 12 452.00 13 457.02 14 470.02

BIOLOGICAL EXAMPLES

The inventive compounds can readily be evaluated to determine activityat The CXCR3 receptors by known methods, such as, for example,Development of Human CXCR3 (N-delta 4) Binding Assay.

Cloning and Expression of Human CXCR3 (N-delta 4):

The DNA encoding human CXCR3 was cloned by PCR using human genomic DNA(Promega, Madison, Wis.) as a template. The PCR primers were designedbased on the published sequence of human orphan receptor GPR9 (1) withincorporated restriction sites, a Kozak consensus sequence, CD8 leaderand Flag tag. The PCR product was subcloned into the mammalianexpression vector pME18neo, a derivative of the SR-alpha expressionvector (designated as pME18Sneo-hCXCR3 (N-delta 4).

IL-3-dependent mouse pro-B cells Ba/F3 were transfected byelectroporation in 0.4 ml Dulbecco's PBS containing 4×10⁶ cells with 20μg of pME18Sneo-hCXCR3 (N-delta 4) plasmid DNA. Cells were pulsed at 400Volts, 100 OHMs, 960 μFd. The transfected cells were under selectionwith 1 mg/ml G418 (Life Technologies, Gaithersburg, Md.). G418-resistantBa/F3 clones were screened for CXCR3 expression by specific binding of[¹²⁵I] IP-10 (NEN Life Science Products, Boston, Mass.).

Preparation of Ba/F3-hCXCR3 (N-delta 4) Membranes

Ba/F3 cells expressing human CXCR3 (N-delta 4) were pelleted andresuspended in the lysis buffer containing 10 mM HEPES, pH 7.5 andComplete® protease inhibitors (1 tablet per 100 ml) (BoehringerMannheim, Indianapolis, Ind.) at a cell density of 20×10⁶ cells per ml.After 5 minutes incubation on ice, cells were transferred to 4639 celldisruption bomb (Parr Instrument, Moline, Ill.) and applied with 1,500psi of nitrogen for 30 minutes on ice. Large cellular debris was removedby centrifugation at 1,000×g. Cell membrane in the supernatant wassedimented at 100,000×g. The membrane was resuspended in the lysisbuffer supplemented with 10% sucrose and stored at −80° C. Total proteinconcentration of the membrane was determined by BCA method from Pierce(Rockford, Ill.).

Human CXCR3 (N-delta 4) Scintillation Proximity Assay (SPA)

For each assay point, 2 μg of membrane was preincubated for 1 hr with300 μg wheat germ agglutinin (WGA) coated SPA beads (Amersham, ArlingtonHeights, Ill.) in the binding buffer (50 mM HEPES, 1 mM CaCl₂, 5 mMMgCl₂, 125 mM NaCl, 0.002% NaN₃, 1.0% BSA) at room temperature. Thebeads were spun down, washed once, resuspended in the binding buffer andtransferred to a 96-well Isoplate (Wallac, Gaithersburg, Md.). 25 pM of[¹²⁵I] IP-10 with tested compounds in a series of titration were addedto start the reaction. After 3 hr reaction at room temperature, theamount of [¹²⁵I] IP-10 bound to the SPA beads was determined with aWallac 1450 Microbeta counter.

The Ki values for the various example compounds of the present inventionare given in the afore-mentioned Table 1. From these values, it would beapparent to the skilled artisan that the compounds of the invention haveexcellent utility CXCR3 antagonists.

While the present invention has been describe in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, medications and variations are intendedto fall within the spirit and scope of the present invention.

Each and every reference referred to in this Application is incorporatedherein by reference in its entirety for all purposes.

1. A compound having the general structure shown in Formula 1:

or a pharmaceutically acceptable salt thereof wherein: G is —C≡N or

X is N; Z is N, or NO; R¹ and R² are independently selected from thegroup consisting of H, alkyl, cycloalkyl, aryl, and hydroxyalkyl; oralternatively, the N taken together with the R¹ and R² forms —N═C(NH₂)₂,R³, R⁵ and R⁶ moieties can be the same or different, each beingindependently selected from the group consisting of H, alkyl, CF₃, OCF₃,haloalkyl, halogen, —N(R³⁰)₂ and —OR³⁰; R⁷ and R⁶ are the same ordifferent, each being independently selected from the group consistingof H, and alkyl; or alternatively R⁷ and R⁸ taken together with thecarbon atom to which they are shown attached is —C═O; the R¹⁰ moietiescan be the same or different, each being independently selected from thegroup consisting of H, alkyl, hydroxyl, —N(R³⁰)₂, —OR³⁰, and halogen; orwherein two R¹⁰ moieties together on the same carbon atom form —C═O; theR¹¹ moieties can be the same or different, each being independentlyselected from the group consisting of H, alkyl, hydroxyl, —N(R³⁰)₂,—OR³⁰, and halogen; or wherein two R¹¹ moieties together on the samecarbon atom form —C═O; R¹² is selected from the group consisting of H,alkyl, haloalkyl and CF₃; D is a phenyl, which is unsubstituted orsubstituted with 1-5 independently selected R²⁰ moieties; the R²⁰moieties can be the same or different, each being independently selectedfrom the group consisting of alkyl, cyano, halogen, haloalkyl,haloalkoxy, —(CH₂)_(q)NH₂, —(CH₂)_(q)NHR³¹, —(CH₂)_(q)N(R³¹)₂, —N(R³⁰)₂,OR³⁰, —SO₂N(R³⁰)₂, and —SO₂(R³¹); Y is selected from the groupconsisting of —(CR¹³R¹³)_(r)—, —CHR¹³C(═O)—, and —C(═O)—; the R¹³moieties can be the same or different, each being independently selectedfrom the group consisting of H, alkyl, cycloalkyl, and alkoxy; the R³⁰moieties can be the same or different, each being independently selectedfrom the group consisting of H and alkyl; the R³¹ moieties areindependently alkyl; m is 0 to 4; n is 0 to 4; each q can be the same ordifferent, each being independently selected from 1 to 5; and r is 1 to4; wherein: “alkyl” refers to C₁-C₆ alkyl; “cycloalkyl” refers to C₃-C₁₀cycloalkyl; and “aryl” refers to C₆-C₁₀ aryl.
 2. The compound accordingto claim 1, wherein G is —C≡N.
 3. The compound according to claim 1,wherein G is


4. The compound according to claim 3, wherein R¹ and R² areindependently selected from the group consisting of H, alkyl,hydroxyalkyl, and cycloalkyl.
 5. The compound according to claim 3,wherein R¹ and R² are independently selected from the group consistingof H, —CH₃, —CH₂CH₃, —CH₂CH₂OH, and cyclopropyl.
 6. The compoundaccording to claim 1, wherein R³ is selected from the group consistingof H, alkyl, alkoxy, halogen, and haloalkyl.
 7. The compound accordingto claim 1, wherein R³ is selected from the group consisting of —H,—CH₃, OCH₃, —Cl and —CF₃.
 8. The compound according to claim 1, whereinR⁵ is selected from the group consisting of H, alkyl, —OR³⁰, —N(R³⁰)₂,and halogen.
 9. The compound according to claim 1, wherein R⁵ isselected from the group consisting of H, CH₃, OH, NH₂, and F.
 10. Thecompound according to claim 8, wherein R⁵ is H.
 11. The compoundaccording to claim 1, wherein R⁶ is selected from the group consistingof H, alkyl, —OR³⁰, —N(R³⁰)₂, and halogen.
 12. The compound according toclaim 1, wherein R⁶ is selected from the group consisting of H andalkyl.
 13. The compound according to claim 1, wherein R⁶ is selectedfrom the group consisting of H, CH₃, OH , NH₂, and F.
 14. The compoundaccording to claim 1, wherein R⁶ is selected from the group consistingof —H and —CH₃.
 15. The compound according to claim 3, wherein R⁷ and R⁸are both H, or R⁷ and R⁸ taken together with the carbon atom to whichthey are shown attached is —C═O.
 16. The compound according to claim 1,wherein R¹⁰ is independently selected from the group consisting ofalkyl, hydroxyl, and alkoxy, or wherein two R¹⁰ moieties together on thesame carbon atom form —C═O, and m is 1-2.
 17. The compound according toclaim 16, wherein R¹⁰ is alkyl, and m is 1-2.
 18. The compound accordingto claim 17, wherein R¹⁰ is selected from the group consisting of —CH₃and —CH₂CH₃.
 19. The compound according to claim 1, wherein R¹¹ isselected from the group consisting of H, alkyl, alkoxy, and hydroxyl, orwherein two R¹¹ moieties together on the same carbon atom form —C═O; andn is 1-2.
 20. The compound according to claim 19, wherein R¹¹ is H, andn is
 1. 21. The compound according to claim 1, wherein R¹² is selectedfrom the group consisting of H, alkyl, and haloalkyl.
 22. The compoundaccording to claim 1, wherein R¹² is selected from the group consistingof H, CH₃, and CF₃.
 23. The compound according to claim 22, wherein R¹²is H.
 24. The compound according to claim 1, wherein Y is selected fromthe group consisting of: —(CHR¹³)_(r)— and —C(═O)—.
 25. The compoundaccording to claim 1, wherein Y is selected from the group consistingof: —CH₂— and —C(═O)—.
 26. The compound according to claim 1, wherein Dis a phenyl optionally substituted with 1-2 R²⁰ moieties selectedindependently from the group consisting of halogen, —OR³⁰, alkyl,—N(R³⁰)₂, haloalkyl, cyano, —SO₂(R³¹), —SO₂N(R³⁰)₂, and haloalkoxy. 27.The compound according to claim 1, wherein D is a phenyl optionallysubstituted with 1-2 R²⁰ moieties selected independently from the groupconsisting of halogen, hydroxyl, alkyl, alkoxy, aminoalkyl, haloalkyl,cyano, sulfonylalkyl, sulfonylamino and haloalkoxy.
 28. The compoundaccording to claim 27, wherein D is a phenyl optionally substituted with1-2 R²⁰ moieties selected independently from the group consisting ofhalogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.
 29. The compoundaccording to claim 1, wherein D is phenyl, substituted with 1-2 moietiesselected independently from the group consisting of alkyl, alkoxy, —Cl,—F, and trifluoromethoxy.
 30. The compound according to claim 1,wherein: G is

R¹ and R² are independently selected from the group consisting of H,alkyl, aryl and cycloalkyl; R³, R⁵, and R⁶ are independently selectedfrom the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl,alkoxy, CF₃, halogen, or hydroxyl; R¹⁰ and R¹¹ are independentlyselected from the group consisting of H, alkyl, —N(R³⁰)₂, halogen, orhydroxyl or wherein two R¹⁰ or R¹¹ moieties together on the same carbonatom form —C═O; and m and n are independently an integer from 1 to 4.31. The compound according to claim 1, wherein: Z is N; G is

X is N; R¹ and R² are independently selected from the group consistingof H, alkyl, and cycloalkyl; R³, R⁵, and R⁶ are independently selectedfrom the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl,alkoxy, CF₃, halogen, and hydroxyl; R⁷ and R⁸ taken together with thecarbon atom to which they are shown attached is —C═O; and m and n areindependently an integer from 1 to
 4. 32. The compound according toclaim 1, wherein: Z is N; G is

X is N; R¹ and R² are independently selected from the group consistingof H, alkyl, and cycloalkyl; R³, R⁵, and R⁶ are independently selectedfrom the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl,alkoxy, CF₃, halogen, and hydroxyl; R⁷ and R⁸ taken together with thecarbon atom to which they are shown attached is —C═O; R¹⁰, R¹¹ areindependently selected from the group consisting of H, alkyl, amino,aminoalkyl, halogen, or hydroxyl or wherein two R¹⁰ or R¹¹ moietiestogether on the same carbon atom form —C═O; and m and n areindependently an integer from 1 to
 4. 33. The compound according toclaim 1, wherein: Z is N; G is

X is N; R¹ and R² are independently selected from the group consistingof H, —CH₃, —CH₂CH₃, cyclopropyl and alkyl; R³, R⁵, R⁶ is independentlyselected from the group consisting of H, —CH₃, —F, —Cl, —OH, —OCH₃,—OCF₃, NH₂, SO₂CH₃, and —CF₃; R⁷ and R⁸ are both H, or R⁷ and R⁸ takentogether with the carbon atom to which they are shown attached is —C═O;R¹⁰ is selected from the group consisting of —CH₃, —CH₂CH₃, andhydroxyl, or two R¹⁰ moieties together on the same carbon atom form ═O,and m is 1-2; R¹¹ is selected from the group consisting of H andhydroxyl or two R¹¹ moieties together on the same carbon atom form —C═O,and n is 1; R¹² is selected from the group consisting of H and CF₃; Y isselected from the group consisting of —CH₂— and —C(═O)—; and D is aphenyl, wherein ring D is substituted with 1-2 moieties selectedindependently from the group consisting of —Cl, —CH₃, —F, —OH, OCH₃,OCF₃, NH₂, NH(CH₃)₂, SO₂CH₃, SO₂NH₂, and trifluoromethyl.
 34. Thecompound according to claim 33, wherein: Z is N; G is

X is N; R¹ and R² are independently selected from the group consistingof H, —CH₃, —CH₂CH₃, cyclopropyl and alkyl; R³, R⁵, R⁶ is independentlyselected from the group consisting of H, —CH₃, —F, —Cl, —OH, —OCH₃,—OCF₃, SO₂CH₃, and —CF₃; R⁷ and R⁸ are both H, or R⁷ and R⁸ takentogether with the carbon atom to which they are shown attached is —C═O;R¹⁰ is selected from the group consisting of —CH₃, —CH₂CH₃, andhydroxyl, or two R¹⁰ moieties together on the same carbon atom form—C═O, and m is 1-2; R¹¹ is selected from the group consisting of H andhydroxyl or two R¹¹ moieties together on the same carbon atom form —C═O,and n is 1; R¹² is selected from the group consisting of H and CF₃; Y isselected from the group consisting of —CH₂— and —C(═O)—; and D is aphenyl, wherein ring D is substituted with 1-2 moieties selectedindependently from the group consisting of —Cl, —CH₃, —F, —OH, NH₂,SO₂CH₃, and trifluoromethoxy.
 35. A compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 36. A compound accordingto claim 1, in optically pure form.
 37. A pharmaceutical compositioncomprising at least one compound of claim 1, or a pharmaceuticallyacceptable salt thereof, in combination with at least onepharmaceutically acceptable carrier.
 38. The pharmaceutical compositionof claim 37, further comprising at least one additional agent, drug,medicament, antibody and/or inhibitor for treating a CXCR3 chemokinereceptor mediated disease.
 39. A pharmaceutical composition comprisingat least one compound of claim 35, or a pharmaceutically acceptablesalt, in combination with at least one pharmaceutically acceptablecarrier.
 40. The pharmaceutical composition of claim 39, furthercomprising at least one additional agent, drug, medicament, antibodyand/or inhibitor for treating a CXCR3 chemokine receptor mediateddisease.